[go: up one dir, main page]

WO2025240499A1 - Treatment of plod2 related diseases and disorders - Google Patents

Treatment of plod2 related diseases and disorders

Info

Publication number
WO2025240499A1
WO2025240499A1 PCT/US2025/029173 US2025029173W WO2025240499A1 WO 2025240499 A1 WO2025240499 A1 WO 2025240499A1 US 2025029173 W US2025029173 W US 2025029173W WO 2025240499 A1 WO2025240499 A1 WO 2025240499A1
Authority
WO
WIPO (PCT)
Prior art keywords
modified
oligonucleotide
sense strand
composition
pyrimidines
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/029173
Other languages
French (fr)
Inventor
Omri GOTTESMAN
Shannon BRUSE
Andrew CICCHETTO
Paul BUSKE
David Lewis
Gregory Mcinnes
Jason O'rourke
David Rozema
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Empirico Inc
Original Assignee
Empirico Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Empirico Inc filed Critical Empirico Inc
Publication of WO2025240499A1 publication Critical patent/WO2025240499A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate

Definitions

  • Osteoarthritis is a common degenerative disease that affects one or more joints in the body. Billions of dollars are spent annually for the treatment of arthritis and for lost days of work associated with the disease. The disease is usually oligoarticular but may be generalized. The joints commonly involved include the hips, knees, lower lumbar and cervical vertebrae, proximal and distal interphalangeal joints of the fingers, first carpometacarpal joints, and first tarsometatarsal joints of the feet. Osteoarthritis is a chronic disease characterized by pathologic, degenerative changes in cartilage, bone, synovium, ligament, muscle, periarticular fat and other joint tissues, leading to pain, swelling, and loss of motion.
  • composition comprising an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount treats an arthropathy.
  • the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof.
  • the treatment of the arthropathy results in, or is intended for, the prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, or a combination thereof.
  • the effective amount of the oligonucleotide improves: a joint function measurement; a joint structure measurement; a pain measurement; an inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement or synovial biomarker measurement; or an osteoarthritis flare-up measurement.
  • the joint function measurement comprises range of motion measurement, morning stiffness duration, or grip strength measurement.
  • the joint function measurement is improved by about 10% or more, as compared to prior to administration.
  • the joint structure measurement comprises a joint space narrowing, osteophyte formation, subchondral sclerosis measurement, or subchondral cyst measurement.
  • the joint structure measurement is improved by about 10% or more, as compared to prior to administration.
  • the inflammation marker measurement comprises a C-reactive protein measurement (CRP), erythrocyte sedimentation rate (ESR) measurement, interleukin (IL)-1 ⁇ , tumor necrosis factor (TNF)- ⁇ , or IL-6 measurement, or a combination thereof.
  • the cartilage biomarker measurement comprises a cartilage oligomeric matrix protein (COMP) measurement, aggrecan measurement, type I collagen measurement, type II collagen measurement, proteoglycan measurement, hyaluronic acid measurement, or a combination thereof.
  • the inflammation marker measurement is improved by about 10% or more, as compared to prior to administration.
  • the cartilage biomarker measurement is improved by about 10% or more, as compared to prior to administration.
  • the bone biomarkers measurement comprises a type II collagen telopeptide fragments (CTX-II) measurement, type I collagen N-telopeptide (NTX-I) measurement, or a combination thereof.
  • CTX-II type II collagen telopeptide fragments
  • NTX-I type I collagen N-telopeptide
  • the bone biomarker measurement is improved by about 10% or more, as compared to prior to administration.
  • the synovial biomarkers measurement comprises a MMP (matrix metalloproteinases) measurement, A Disintegrin and Metalloprotease with Thrombospondin motifs (ADAMTS) measurement, a number of pyridinoline cross-links per triple helix collagen measurement, or a combination thereof.
  • the synovial biomarker measurement is improved by about 10% or more, as compared to prior to administration.
  • the oligonucleotide comprises a modified internucleoside linkage.
  • the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.
  • the oligonucleotide comprises a modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’,4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2'-O-alkyl, 2’-C-allyl, 2’-O-allyl, 2'-fluoro, or 2'- deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof.
  • LNA locked nucleic acid
  • HNA hex
  • the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl - 2 - Attorney Docket No.54462-772.601 stearyl, ⁇ -tocopherol, stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof.
  • the lipid comprises a lipid moiety comprising ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety comprises ETL20.
  • the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar comprises N-acetylgalactosamine (GalNAc), N- acetylglucosamine (GlcNAc), or mannose.
  • the oligonucleotide comprises an integrin or integrin targeting ligand attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the integrin comprises integrin alpha-v-beta-6 or integrin alpha-v-beta-3 ( ⁇ v ⁇ 3) or a combination thereof.
  • the integrin targeting ligand comprises an arginine-glycine- aspartic acid (RGD) peptide.
  • the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • the sense strand is 12-30 nucleosides in length.
  • the antisense strand is 12-30 nucleosides in length.
  • the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the composition is administered by an intra-articular administration.
  • composition comprising an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises: an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1.
  • siRNA comprising a sense strand and an antisense strand
  • each strand is independently about 12-30 nucleosides in length
  • at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1
  • ASO antis
  • the sense sequence comprises a modification pattern selected from the group consisting of 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S,
  • the antisense sequence comprises a modification pattern selected from the group consisting of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • any one of the following is true with regard to the sense - 3 - Attorney Docket No.54462-772.601 strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyr
  • any one of the following is true with regard to the antisense strand: all purines comprise 2’- fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidine
  • any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyr
  • composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a sequence of Table 3.
  • composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41
  • compositions comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS,
  • composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1; wherein the ASO comprises - 5 - Attorney Docket No.54462-772.601 modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41
  • ASO antisense oligonucleot
  • the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof.
  • the method comprises an intra-articular administration of the effective amount of the composition.
  • the intra-articular administration is ultrasound guided.
  • FIG.1 shows western blots from transfected cells. Whole cell protein lysates were evaluated for intracellular PLOD2 protein (left) and cell culture media supernatants were evaluated for extracellular PLOD2 protein (right).
  • Lysate rows 1-4 (left to right): Empty, WT (wildtype), S166Ter, and R495Ter.
  • Supernatent rows 5-8 (left to right): Empty, WT (wildtype), S166Ter, and R495Ter. Positions for molecular weights 150, 100, 75, 50, 20, and 15 are shown. The top boxes correspond to staining with anti- FLAG antibodies while the bottom (left) box corresponds to the GAPDH control.
  • DETAILED DESCRIPTION [0014] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development.
  • a Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample.
  • a GWAS may enable better understanding of the biology of - 6 - Attorney Docket No.54462-772.601 disease and provide applicable treatments.
  • a GWAS can utilize genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome.
  • the most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease.
  • Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size.
  • allelic odds ratio is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele).
  • An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.” [0015] Functional annotation of variants and/or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease-causing genes.
  • understanding the functional effect of a causal genetic variant may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.
  • Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry.
  • disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics.
  • therapeutic modalities There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines.
  • PLOD2 procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 is located on human chromosome 3 (3q24), and also contains 19 exons. PLOD2 may include 737 amino acids and have a mass of about 84686 Da.
  • PLOD2 is an enzyme that post-translationally modifies collagen by hydroxylating lysine residues in collagen molecules. This modification is crucial for the stability and cross-linking of collagen fibers within the extracellular matrix (ECM). The hydroxylation of lysine residues enables further glycosylation by COLGALT2 (collagen beta(1-O)galactosyltransferase 2).
  • COLGALT2 collagen beta(1-O)galactosyltransferase 2
  • PLOD2 may be intracellular.
  • PLOD2 may be extracellular.
  • PLOD2 may be expressed in chondrocytes.
  • PLOD2 may be expressed in osteoblasts.
  • PLOD2 may be expressed in fibroblasts.
  • PLOD2 may be expressed in synoviocytes.
  • PLOD2 may be expressed in articular joint.
  • the sense strand comprises any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 or the antisense strand comprises any one of SEQ ID NOs: 3733- 7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189.
  • the sense strand or the antisense strand comprises any of modification patterns 1S to 155S or 1AS to 69AS.
  • the sense strand or the antisense strand comprises any of modification patterns 54S, 58S, 7AS, 51AS, or 46AS.
  • the sense strand comprises modification pattern 54S.
  • the sense strand comprises modification pattern 58S. In some embodiments, the antisense strand comprises modification pattern 7AS. In some embodiments, the antisense strand comprises modification pattern 46AS. In some embodiments, the antisense strand comprises modification pattern 51AS. - 8 - Attorney Docket No.54462-772.601 I. COMPOSITIONS [0022] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets PLOD2. In some embodiments, the composition consists of an oligonucleotide that targets PLOD2.
  • Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein.
  • Some embodiments include a composition comprising an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases PLOD2 mRNA or PLOD2 protein levels in a cell, fluid or tissue.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases PLOD2 mRNA levels in a cell or tissue.
  • the cell is a chondrocyte, an osteoblast, a synoviocyte, or a fibroblast.
  • the tissue is articular joint tissue. In some embodiments, the tissue is articular cartilage. In some embodiments, the tissue is synovium. In some embodiments, the tissue is synovial membrane. In some embodiments, the fluid is synovial fluid. In some embodiments, the PLOD2 mRNA levels are each decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by about 10% or more, as compared to prior to administration.
  • the PLOD2 mRNA levels are each decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the PLOD2 protein levels are each decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration.
  • the adverse phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the protective phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the protective phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration.
  • the joint function measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration.
  • the joint function measurement is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 10%, as compared to prior to administration.
  • the joint function measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration.
  • the joint function measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • a joint structure may be affected by an arthropathy.
  • some inflammatory arthropathies that may include osteoarthritis, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, or degenerative joint disease that may lead to joint space narrowing, osteophyte formation, subchondral sclerosis, or subchondral cysts that may be treated using a composition comprising an oligonucleotide.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount change or improves a joint structure measurement of the subject.
  • the joint structure measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the joint structure measurement includes a joint space measurement e.g., joint space narrowing measurement.
  • joint space narrowing As cartilage deteriorates or wears away, narrowing of the joint space of the affected joint can be observed (joint space narrowing).
  • joint space width (JSW) measurements are often considered a surrogate for articular cartilage thickness as such measurements involve determining the distance between two bones (e.g., using X-ray techniques). Without being bound by any theory, an increase in the JSW is an indicator of cartilage growth. Methods of measurement of JSW can be completed following radiographic imaging of the affected joint.
  • JSW measurements can be either manual using calipers or a simple graduated ruler and a micrometric eyepiece or semiautomated using computer software.
  • JSW measurements can involve radiographic images (e.g., X-ray) taken of the knee.
  • radiographic images e.g., X-ray
  • AP semiflexed anteroposterior
  • Lyon-Schuss radiographs can be used to obtain the measurement.
  • the subject is imaged while standing.
  • the joint structure measurement includes osteophyte formation.
  • the joint structure measurement includes subchondral sclerosis measurement.
  • the joint structure measurement includes subchondral cysts measurement.
  • the measurement includes measuring the volume, area, depth of osteophytes, subchondral cysts, or subchondral sclerosis.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves osteophyte formation in the subject.
  • the osteophyte formation is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the osteophyte formation is improved by about 10% or more, as compared to prior to administration.
  • the osteophyte formation is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves subchondral sclerosis in the subject.
  • the subchondral sclerosis is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by about 10% or more, as compared to prior to administration.
  • the subchondral sclerosis is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by no more than about 10%, as compared to prior to administration.
  • the subchondral sclerosis is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves subchondral cysts in the subject.
  • the subchondral cysts are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the subchondral cysts are improved by about 10% or more, as compared to prior to administration.
  • the subchondral cysts are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration.
  • the subchondral cysts are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration.
  • the subchondral cysts are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases pain (as assessed by visual analogue scale (VAS), WOMAC pain subscale) in the subject.
  • VAS visual analogue scale
  • WOMAC pain subscale WOMAC pain subscale
  • the pain is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the pain is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the pain is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the pain is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the pain is decreased by no more than about 10%, as compared to prior to administration.
  • the pain is decreased by no more than about 20%, no more - 14 - Attorney Docket No.54462-772.601 than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration.
  • the pain is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves (e.g., decreases) the levels of inflammation markers in the subject.
  • inflammation markers include, but are not limited to, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1 ⁇ , tumor necrosis factor (TNF)- ⁇ , and IL-6.
  • CRP C-reactive protein
  • ESR erythrocyte sedimentation rate
  • IL-1 ⁇ interleukin-1 ⁇
  • TNF tumor necrosis factor
  • IL-6 interleukin-1 ⁇
  • the levels of inflammation markers are improved by about 10% or more, as compared to prior to administration.
  • the levels of inflammation markers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by no more than about 10%, as compared to prior to administration.
  • the levels of inflammation markers are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves the levels of cartilage biomarkers in the subject.
  • cartilage biomarker include, but are not limited to, Cartilage Oligomeric Matrix Protein (COMP), aggrecan, type I collagen, type II collagen, proteoglycans or hyaluronic acid.
  • the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the levels of cartilage biomarkers are improved by about 10% or more, as compared to prior to administration.
  • the levels of cartilage biomarkers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by no more than about 10%, as compared to prior to administration.
  • the levels of cartilage biomarkers are improved by no more than about 20%, no more - 15 - Attorney Docket No.54462-772.601 than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration.
  • the levels of cartilage biomarkers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves the levels of synovial biomarkers in the subject.
  • synovial biomarkers include, but are not limited to, matrix metalloproteinases (MMPs), disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS), and the number of pyridinoline cross-links per triple helix collagen.
  • Cartilage destruction in osteoarthritis is thought to be mediated by two main enzyme families; the matrix metalloproteinases (MMPs) are responsible for cartilage collagen breakdown, whereas enzymes from the 'a disintegrin and metalloproteinase domain with thrombospondin motifs' (ADAMTS) family mediate cartilage aggrecan loss.
  • MMPs matrix metalloproteinases
  • ADAMTS thrombospondin motifs'
  • the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the levels of synovial biomarkers are improved by about 10% or more, as compared to prior to administration.
  • the levels of synovial biomarkers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by no more than about 10%, as compared to prior to administration.
  • the levels of synovial biomarkers are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a patient-reported outcome measurement (PROMs) including, but not limited to, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Medical Outcome Studies Short Form 36 (SF-36), Knee Disability and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), Disabilities of the Arm, Shoulder and Hand (DASH), EUROQoL (EQ5-D), Medical Outcomes Study Short Form 12-item (SF12), Hip Disability and Osteoarthritis Outcome Score (HOOS), Pain Catastrophizing (PCS) and Oxford Hip Score (OHS) in the subject.
  • PROMs patient-reported outcome measurement
  • the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or - 16 - Attorney Docket No.54462-772.601 more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a physical function measurement in the subject, including, but not limited to, 6-minute walk test, timed up-and-go test.
  • the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration.
  • the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 10%, as compared to prior to administration.
  • the measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a quality-of-life assessment or measurement in the subject, including, but not limited to, Medical Outcome Studies Short Form 36 (SF- 36), EUROQoL (EQ-5D).
  • the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration.
  • the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 10%, as compared to prior to administration.
  • the measurement is improved by no - 17 - Attorney Docket No.54462-772.601 more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves (e.g., decreases) osteoarthritis flare-ups (i.e. exacerbations) in the subject.
  • the flare-ups are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the flare-ups are improved by about 10% or more, as compared to prior to administration.
  • the flare-ups are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the flare-ups are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the flare-ups are improved by no more than about 10%, as compared to prior to administration.
  • the flare-ups are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the flare-ups are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves radiographic progression (assessed by Kellgren-Lawrence grading scale) in the subject.
  • the progression is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the progression is improved by about 10% or more, as compared to prior to administration.
  • the progression is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration.
  • the progression is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the progression is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the progression is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration.
  • the progression is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • - 18 Attorney Docket No.54462-772.601 A.
  • siRNAs [0042]
  • the composition comprises an oligonucleotide that targets PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA).
  • the composition comprises an oligonucleotide that targets PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • siRNA small interfering RNA
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length.
  • the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the sense strand may be 14-30 nucleosides in length.
  • the composition comprises an antisense strand is 12-30 nucleosides in length.
  • the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the antisense strand may be 14-30 nucleosides in length.
  • At least one of the sense strands and the antisense strands comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 1.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 1.
  • any of the aforementioned siRNAs may include a sense strand of SEQ ID NO: 1, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A.
  • Any of the aforementioned siRNAs may include an antisense strand of SEQ ID NO: 1, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand of the composition 5’ 7 -3’ and an antisense strand of composition 5 7 -3’.
  • (N) 0-7 are independently nucleic acid stretches of 0 to 7 nucleotides, ( ) contain at least 15 contiguous nucleotides from Tables 3-5 and contain no cyclic ribose nucleotides with 2’ hydroxyl groups.
  • the sense and antisense strand have 1-5 phosphorothioate inter-nucleotide linkages and either the sense or antisense strand has a targeting ligand attached to the 5’ or 3’ end.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand composition.
  • the targeting ligand may be a lipid - 19 - Attorney Docket No.54462-772.601 moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand.
  • LRP lipoprotein receptor related protein
  • TfR transferrin receptor
  • GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal- 6]s[Gal-6]s[Gal-6], Janssen, Arbutus THA.
  • the GalNAc moiety is ETL17.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex.
  • the first base pair of the double-stranded RNA duplex is an AU base pair.
  • the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a - 20 - Attorney Docket No.54462-772.601 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate PLOD2 mRNA.
  • the siRNA binds with a huma PLOD2 mRNA and less than or equal to 10 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 20 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 30 human off-target transcripts, with no more than 3 mismatches in the antisense strand.
  • the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182- 8185 in PLOD2.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, at least 80% identical to any one of SEQ ID NOs: 2-3732 in PLOD2, at least 85% identical to of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, at least 90% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or at least 95% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2.
  • the 5’ overhang comprises 2 nucleosides.
  • the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2.
  • the sense strand sequence - 21 - Attorney Docket No.54462-772.601 may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2-3732, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise an overhang.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the sense strand may comprise an integrin or an integrin-targeting ligand.
  • the sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, or LDL receptor ligand.
  • LRP lipoprotein receptor related protein
  • TfR transferrin receptor
  • the sense strand may comprise an integrin or an integrin targeting ligand.
  • the sense strand may comprise an angiopep-2.
  • the sense strand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the sense strand may comprise a glucose transporter protein.
  • the sense strand may comprise an LDL receptor ligand.
  • any of the aforementioned siRNAs may include a strand where the 5’ nucleoside has been modified to an A.
  • Any one of the aforementioned siRNAs may include a strand sequence wherein the 5’ nucleoside has been modified to a U or T.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A, T, C, U, or G.
  • position 5 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732 in PLOD2 is modified to - 22 - Attorney Docket No.54462-772.601 an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 2- 3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112- 8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 2- 3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, at least 80% identical to any one of SEQ ID NOs: 3733-7463 in PLOD2, at least 85% identical to of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, at least 90% identical to any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, or at least 95% identical to any one of SEQ ID NOs: 3733-7463 in PLOD2.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2.
  • the antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3733-7463 in PLOD2, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences.
  • the antisense strand may comprise an overhang.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, or LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167- 8173, or 8186-8189 in PLOD2.
  • the antisense strand may comprise an integrin or an integrin targeting ligand.
  • the antisense strand may comprise an angiopep-2.
  • the antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the antisense strand may comprise a glucose transporter protein.
  • the antisense strand may comprise an LDL receptor ligand.
  • Any of the aforementioned siRNAs may include a strand wherein the 3’ nucleoside has been modified to an A.
  • Any one of the aforementioned siRNAs may include a strand sequence wherein the 3’ nucleoside has been modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: - 24 - Attorney Docket No.54462-772.601 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an A.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an A.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an C.
  • any of the aforementioned siRNA comprising a sense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein - 25 - Attorney Docket No.54462-772.601 receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NOs: 1-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the sense strand may comprise an integrin or an integrin targeting ligand.
  • the sense strand may comprise an angiopep-2.
  • the sense strand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the sense strand may comprise a glucose transporter protein.
  • the sense strand may comprise an LDL receptor ligand.
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA.
  • the GalNAc moiety is ETL17.
  • lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • any of the aforementioned siRNA comprising an antisense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189.
  • LRP lipoprotein receptor related protein
  • TfR transferrin receptor
  • the antisense stand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the antisense strand may comprise an integrin or an integrin targeting ligand.
  • the antisense strand may comprise an angiopep- 2.
  • the antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the antisense strand may comprise a glucose transporter protein.
  • the antisense strand may comprise an LDL receptor ligand.
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA.
  • the GalNAc moiety is ETL17.
  • lipid moiety comprises including, but not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense - 26 - Attorney Docket No.54462-772.601 strand or antisense strand sequence of subset A.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A. The sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A.
  • any of the aforementioned siRNAs may include a sense strand of subset A, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A.
  • Any of the aforementioned siRNAs may include an antisense strand of one of subset A, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B.
  • any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand of subset B, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset B, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C. The sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E.
  • any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand of subset E, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A.
  • any of the aforementioned siRNAs may include an antisense strand of one of subset E, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset F.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F. The sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset F.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset F.
  • Any of the aforementioned siRNAs may include a sense strand of - 29 - Attorney Docket No.54462-772.601 subset F, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A.
  • any of the aforementioned siRNAs may include an antisense strand of one of subset F, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset G.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset G.
  • any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand of subset G, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset G, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • any of the aforementioned siRNA comprising a sense strand or antisense stand comprises a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense or anti sense strand sequence of one of subset A, subset B, subset C, subset D, subset E, or subset F.
  • the sense strand or antisense stand may comprise a lipid moiety.
  • the sense or antisense strand may comprise a GalNAc moiety.
  • the sense strand or antisense stand may comprise an integrin or an integrin targeting ligand.
  • the sense strand or antisense stand may comprise an angiopep-2.
  • the sense strand or antisense stand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the antisense strand may comprise a glucose transporter protein.
  • the sense strand or antisense stand may comprise an LDL receptor ligand.
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA.
  • the GalNAc moiety is ETL17.
  • lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4.
  • the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.
  • a sense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the 3’ nucleoside to an A.
  • a sense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end).
  • an antisense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the 5’ nucleoside to an U.
  • Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end).
  • siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA may comprise the sense strand and/or the antisense strand base sequence (e.g., unmodified sequence, or base sequence with other modifications) of an siRNA in any table included herein; or may include a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; or may include a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sequence does not include an overhang (e.g., UU) that is included in a table.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A (Table 3-SubsetA), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A.
  • the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end).
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. - 31 - Attorney Docket No.54462-772.601 [0068]
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B (Table 3-SubsetB), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B.
  • the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0069]
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C (Table 3-Subset C), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D (Table 3-Subset D), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D.
  • the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned - 32 - Attorney Docket No.54462-772.601 siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0071]
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E (Table 3-Subset E), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F (Table 3-Subset F), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F.
  • the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end).
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length.
  • the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human PLOD mRNA sequence such as SEQ ID NO: 1; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human PLOD mRNA sequence such as SEQ ID NO: 1; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a
  • the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 1.
  • C. Modified oligonucleotides [0075]
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • a phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur.
  • Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include improved toxicity or improved pharmacokinetics.
  • the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs.
  • the duplex comprises blunt-ends at the 5’or 3’ ends of each strand.
  • One strand (antisense strand) is complementary to a target mRNA.
  • Each end of the antisense strand has one to five phosphorothioate bonds.
  • the 5’ end has an optional phosphate mimic such as a vinyl phosphonate.
  • the oligonucleotide is used to knock down a target mRNA or a target protein.
  • the sense strand has the same sequence as the target mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers.
  • the oligonucleotide comprises no more than 18 modified internucleoside linkages.
  • the oligonucleotide comprises no more than 20 modified internucleoside linkages.
  • the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or - 34 - Attorney Docket No.54462-772.601 more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside link
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises the modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), 2’,4’ constrained ethyl nucleic acid, hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2’-C-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.
  • LNA locked nucleic acid
  • HNA hexitol nucleic acid
  • CeNA cyclohexene nucleic acid
  • the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O- alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group.
  • the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside.
  • the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside.
  • the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics. [0079] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure: - 35 - Attorney Docket No.54462-772.601 wherein the base can be any pyrimidine or purine. [0080] An unlocked nucleic acid may comprise the following structure: wherein the base can be any pyrimidine or purine.
  • the oligonucleotide comprises a modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid and an abasic site: are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.
  • the oligonucleotide comprises a phosphate mimic.
  • the phosphate mimic comprises methylphosphonate.
  • An example of a nucleotide that comprises a methylphosphonate is shown below: methylphosphonate 2’-O-methyl Uridine).
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides.
  • the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.
  • the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.
  • the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl.
  • each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications.
  • each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof.
  • the oligonucleotide may include pyrimidines.
  • pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.
  • the sense strand comprises purines and pyrimidines.
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl.
  • all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl.
  • all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl.
  • the sense strand may include a 2’-deoxy nucleoside. [0089] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside.
  • At least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside.
  • At least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- - 38 - Attorney Docket No.54462-772.601 methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro.
  • all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.
  • Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; an overhang region at the 3 end of the sense strand having at least 3 contiguous phosphorothioated nucleotides; and an overhang region at the 3' end of the antisense strand having at least 3 contiguous phosphorothioated nucleotides.
  • Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; and an overhang region at the 3’ end of the sense strand having at least 3 contiguous phosphorothioated nucleotides.
  • the oligonucleotide includes two to eight oligonucleotides attached through a linker. The linker may be hydrophobic.
  • the oligonucleotides independently have substantial chemical stabilization (e.g., at least 40% of the constituent bases are chemically-modified). In some embodiments, the oligonucleotides have full chemical stabilization (i.e., all of the constituent bases are chemically-modified). In some embodiments, the oligonucleotide includes one or more single-stranded phosphorothioated tails, each independently having two to twenty nucleotides. In some embodiments, each single-stranded tail has eight to ten nucleotides.
  • a compound (e.g., moiety attached to the oligonucleotide) includes three properties: (1) a branched structure, (2) full metabolic stabilization, and (3) the presence of a single- stranded tail comprising phosphorothioate linkers.
  • a compound has 2 or 3 branches. The increased overall size of the branched structures promote increased uptake. Also, without being bound by a particular theory of activity, multiple adjacent branches (e.g., 2 or 3) allow each branch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release.
  • the compound may include an oligonucleotide described herein, as part of the compound.
  • a compound includes the following properties: (1) two or more branched oligonucleotides linked via a non-natural linker (2) substantially chemically stabilized, e.g., wherein more than 40%, optimally 100%, of oligonucleotides are chemically modified (e.g., no RNA and optionally no DNA); and (3) phosphorothioated single oligonucleotides containing at least 3, optimally 5- 20 phosphorothioated bonds.
  • the oligonucleotide comprises a phosphate at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate at a 3’ end.
  • the - 39 - Attorney Docket No.54462-772.601 oligonucleotide comprises a phosphate mimic at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 3' end.
  • the oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof.
  • the oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines.
  • all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.
  • pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines.
  • pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl - 40 - Attorney Docket No.54462-772.601 modified pyrimidines.
  • all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • the oligonucleotide comprises a particular modification pattern.
  • position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification.
  • position 9 of a strand of the oligonucleotide is a pyrimidine
  • all purines in a strand of the oligonucleotide have a 2’OMe modification.
  • position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide.
  • both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.
  • position 9 of a strand of the oligonucleotide when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.
  • position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.
  • the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group.
  • the targeting group includes a cell receptor ligand, such as an integrin targeting ligand.
  • Integrins may include a family of transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion.
  • the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) bay be an example of an epithelial-specific integrin ⁇ v ⁇ 6 may be a receptor for an ECM protein or TGF-beta latency-associated peptide (LAP).
  • Integrin ⁇ v ⁇ 6 may be expressed in a cell or tissue. Integrin ⁇ v ⁇ 6 may be expressed or upregulated in injured pulmonary epithelium.
  • the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin ⁇ v ⁇ 6.
  • An integrin targeting ligand may include a compound that has affinity for integrin ⁇ v ⁇ 6 or integrin alpha-v-beta-3 ( ⁇ v ⁇ 3), may be useful as a ligand to facilitate targeting or delivery of the oligonucleotide to which it is attached to a particular cell type or tissue (e.g., to cells expressing integrin ⁇ v ⁇ 3 or ⁇ v ⁇ 6).
  • multiple integrin targeting ligands are linked to the oligonucleotide.
  • the oligonucleotide-integrin targeting ligand conjugates are selectively internalized by chondrocytes, either through receptor-mediated endocytosis or by other means.
  • Examples of targeting groups useful for delivering the oligonucleotide that include integrin targeting ligands may be based upon peptides or peptide mimics containing an arginine-glycine-aspartic acid (RGD) peptide.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an RGD peptide.
  • the composition comprises an RGD peptide.
  • the composition comprises an RGD peptide derivative.
  • the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide.
  • the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the oligonucleotide comprises an RGD peptide, and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the RGD peptide may be linear.
  • the RGD peptide may be cyclic.
  • An RGD peptide may include a D-amino acid.
  • - 42 - Attorney Docket No.54462-772.601 the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys).
  • the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys).
  • the RGD peptide comprises Cyclo(- Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides.
  • the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all pyrimidines of the oligonucleotide comprise 2’-O-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-methyl modified pyrimidines. [00110] In some cases, position 9 of a strand of the oligonucleotide can be a 2’-deoxy. In these cases, 2’-F and 2’-OMe modifications may occur at the other positions of a strand of the oligonucleotide.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine.
  • all purines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row.
  • the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- - 43 - Attorney Docket No.54462-772.601 numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises a 2’-fluoro-modified purine.
  • all pyrimidines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row.
  • the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide.
  • position nine of the sense strand comprises a 2’- fluoro-modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.
  • the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5’-end group.
  • the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein.
  • the 5’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’-end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl.
  • the 5’-end group may comprise 5’-VP.
  • the 5’-VP comprises a trans-vinylphosphonate or cis-vinylphosphonate.
  • the 5’-end group may include an extra 5’ phosphate.
  • a combination of 5’-end groups may be used.
  • the oligonucleotide includes a negatively charged group.
  • the negatively charged group may aid in cell or tissue penetration.
  • the negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group.
  • the end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl.
  • the end group may include an extra 5’ phosphate such as an extra 5’ phosphate.
  • a combination of end groups may be used.
  • the oligonucleotide includes a phosphate mimic.
  • the phosphate mimic comprises vinyl phosphonate.
  • the vinyl phosphonate comprises a trans-vinylphosphonate.
  • the vinyl phosphonate comprises a cis-vinylphosphonate.
  • the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.
  • the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • Hydrophobic moieties [00120] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a hydrophobic moiety.
  • the hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the hydrophobic moiety may include a lipid such as a fatty acid.
  • the hydrophobic moiety may include a hydrocarbon.
  • the hydrocarbon may be linear.
  • the hydrocarbon may be non-linear.
  • the hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or ⁇ -tocopherol, or a combination thereof.
  • the lipid comprises stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof.
  • the oligonucleotide comprises a lipophilic moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis- Othexadecyl glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoy)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or a combination thereof.
  • the lipophilic moiety may include a steroid such as cholesterol.
  • the lipophilic moiety may include retinoic acid.
  • the lipophilic moiety may include cholic acid.
  • the lipophilic moiety may include adamantane acetic acid.
  • the lipophilic moiety may include 1-pyrene butyric acid.
  • the lipophilic moiety may include dihydrotestosterone.
  • the lipophilic moiety may include 1,3-bis-O(hexadecyl) glycerol.
  • the lipophilic moiety may include geranyloxyhexyanol.
  • the lipophilic moiety may include hexadecylglycerol.
  • the lipophilic moiety may - 46 - Attorney Docket No.54462-772.601 include borneol.
  • the lipophilic moiety may include menthol.
  • the lipophilic moiety may include 1,3- propanediol.
  • the lipophilic moiety may include a heptadecyl group.
  • the lipophilic moiety may include palmitic acid.
  • the lipophilic moiety may include myristic acid.
  • the lipophilic moiety may include O3- (oleoy]lithocholic acid.
  • the lipophilic moiety may include O3-(oleoyl)cholenic acid.
  • the lipophilic moiety may include ibuprofen.
  • the lipophilic moiety may include naproxen.
  • the lipophilic moiety may include dimethoxytrityl.
  • the lipophilic moiety may include phenoxazine.
  • the lipophilic moiety comprises a hydrocarbon chain.
  • the hydrocarbon chain may comprise or consist of a C 4 -C 30 hydrocarbon chain.
  • the lipophilic moiety comprises a lipid.
  • the oligonucleotide includes one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand of the oligonucleotide, optionally via a linker or carrier.
  • an oligonucleotide comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via a linker or carrier.
  • the lipophilicity of the lipophilic moiety measured by octanol-water partition coefficient, logP, exceeds 0.
  • the lipophilic moiety is an aliphatic, cyclic such as alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol), a linear or branched aliphatic hydrocarbon, or an aromatic.
  • Exemplary lipophilic moieties may include lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O-(hexadecyl) glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine.
  • Suitable lipophilic moieties may also include those containing a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl), and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.
  • the functional group may be useful to attach the lipophilic moiety to the oligonucleotide.
  • the lipophilic moiety contains a saturated or unsaturated C6- C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl).
  • the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a hydrophobic ligand or moiety.
  • the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative.
  • the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and/or an antisense strand of a siRNA).
  • a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid. [00128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or ⁇ -tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, litrocholyl, docosanyl, docosahexaenyl, or myristyl.
  • the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified. [00129] In some embodiments, the oligonucleotide comprises any aspect of the following structure: .
  • the oligonucleotide comprises any aspect of the following structure: . some embodiments, the oligonucleotide comprises any aspect of the following structure: - 48 - Attorney Docket No.54462-772.601 . In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group.
  • the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 18 carbons.
  • the oligonucleotide does not comprise a phenyloctyl group.
  • the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons.
  • R is not an octane (C8). In some embodiments, R includes a branched carbon chain.
  • R includes an unbranched carbon chain.
  • the lipid moiety comprises an alcohol or ether.
  • the lipid moiety has at least one degree of unsaturation.
  • the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid.
  • the lipid includes a fatty acid.
  • the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety.
  • a lipid moiety in Table 1 may be attached at a different point of attachment than shown.
  • the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end.
  • the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.
  • the lipid or lipid moiety includes 16 to 18 carbons.
  • the lipid includes 16 carbons.
  • the lipid includes 17 carbons.
  • the lipid includes 18 carbons.
  • the lipid moiety includes 16 carbons.
  • the lipid moiety includes 17 carbons.
  • the lipid moiety - 49 - Attorney Docket No.54462-772.601 includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons.
  • Table 1 Hydrophobic moiety examples - 50 - Attorney Docket No.54462-772.601 - 51 - Attorney Docket No.54462-772.601 - 52 - Attorney Docket No.54462-772.601 [00132]
  • the hydrophobic moiety may include a linker that comprises a carbocycle.
  • the carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl.
  • the linker may include a phenyl.
  • the linker may include a cyclohexyl.
  • the lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide.
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration).
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration).
  • the lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.
  • the lipid moiety may comprise or consist of the following structure: .
  • the lipid moiety comprises or consists of the following structure: . some embodiments, the lipid moiety comprises the following some embodiments, the lipid moiety comprises or consist of the following structure: . some embodiments, the dotted line indicates a covalent connection.
  • the covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand.
  • n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons.
  • R comprises or consists of an alkyl group containing 4-18 carbons. In some embodiments, R is not octane. In some embodiments, R is a carbon containing 4-7 or 9-18 carbons.
  • the lipid moiety is not a phenyloctyl group.
  • the 5’ hydrophobic moiety comprises any one of the following line indicates a covalent connection to the end of the 5’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane.
  • the alkyl group contains 4–7 or 9–18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons.
  • the alkyl group contains 18 carbons.
  • the 5’ hydrophobic moiety comprises a hydrophobic moiety in Table 1.
  • the 5’ hydrophobic moiety comprises phenyl para C12.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.
  • n is 0–3.
  • n is 1–3.
  • n is 1.
  • n is 2.
  • the hydrophobic moiety comprises an alcohol or an ether.
  • R is an unsaturated alkyl group.
  • the unsaturated alkyl group may be monounsaturated.
  • the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof.
  • the 5’ hydrophobic moiety is not a phenyloctyl group.
  • the hydrophobic moiety may include a linker that comprises a carbocycle.
  • the carbocycle may be six-membered.
  • Some examples of a carbocycle include phenyl or cyclohexyl.
  • the linker may include a phenyl.
  • the linker may include a cyclohexyl.
  • the lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide.
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl - 54 - Attorney Docket No.54462-772.601 linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration).
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration).
  • the lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.
  • R is an unsaturated hydrocarbon.
  • R is a monounsaturated acyl group.
  • the monounsaturated acyl group is unsaturated at the omega-3, omega-5, omega-6, omega-7, omega-8, or omega-9 position.
  • the unsaturated hydrocarbon is a polyunsaturated fatty acyl group.
  • the polyunsaturated fatty acyl group is unsaturated at least at the omega-3, omega-5, omega-6, omega-7, omega-, omega-9 position, or a combination thereof.
  • the lipid moiety may be attached at a 5’ end of the oligonucleotide.
  • the 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety.
  • the 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety.
  • the 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety.
  • the sugar may include a ribose.
  • the sugar may include a deoxyribose.
  • the sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose).
  • a phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.
  • Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate.
  • a strategy for making hydrophobic conjugates may include use of a - 55 - Attorney Docket No.54462-772.601 phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol.
  • the phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate.
  • Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows: . n some embodiments, n is 1-3.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.
  • any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety.
  • the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA.
  • the sense strand may then be hybridized to an antisense strand to form a duplex.
  • the hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature.
  • the temperature may be gradually reduced.
  • the temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands.
  • the temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands.
  • the temperature may be below a melting temperature of the sense and antisense strands.
  • - 56 Attorney Docket No.54462-772.601
  • the lipid may be attached to the oligonucleotide by a linker.
  • the linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).
  • the modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition.
  • the modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue. 2.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a sugar moiety.
  • the sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety.
  • the sugar moiety may include 1, 2, 3, or more sugar molecules.
  • the sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar moiety may include an N-acetyl galactose moiety.
  • the sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety.
  • the sugar moiety may include an N-acetyl glucose moiety.
  • the sugar moiety may include N-acetylglucosamine (GlcNAc) moiety.
  • the sugar moiety may include a fucose moiety.
  • the sugar moiety may include a mannose moiety.
  • N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206.
  • the sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte.
  • the GalNAc moiety may bind to an asialoglycoprotein receptor.
  • the GalNAc moiety may target a hepatocyte.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or trivalent branched linker.
  • the oligo may be attached to 1, 2, or 3 GalNAcs through a bivalent or trivalent branched linker.
  • the GalNAc moiety may include 1, 2, 3, or more GalNAc molecules.
  • the GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.
  • GalNAc N-acetylgalactosamine
  • the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.
  • compositions comprising an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a GalNAc moiety.
  • the GalNAc - 57 - Attorney Docket No.54462-772.601 moiety may be included in any formula, structure, or GalNAc moiety shown below.
  • a compound e.g., oligonucleotide represented by Formula (I) or (II): or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR 6 , or if z is 1, Y is C(R 6 )2; Q is selected from: C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR 7 , -SR 7
  • z is 3 and Y is C.
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , - N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 .
  • Q is selected from C 5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2.
  • Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 , and -NH 2 .
  • Q is selected from phenyl.
  • Q is selected from cyclohexyl.
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, - OP(O)(OR 7 )S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2- - 59 - Attorney Docket No.54462-772.6
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O- )S-, and -OP(OR 7 )O-.
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and -OP(OR 7 )O-. In some embodiments, R 1 is selected from - OP(O)(OR 7 )O- and -OP(OR 7 )O-.
  • R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , and -S(O)R 7 .
  • R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 ) 2 .
  • R 2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR 7 and - OC(O)R 7 .
  • R 3 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 . In some embodiments, R 3 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2. In some embodiments, R 3 is selected from -OR 7 - and -OC(O)R 7 .
  • R 4 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 . In some embodiments, R 4 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2. In some embodiments, R 4 is selected from -OR 7 - and -OC(O)R 7 .
  • R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 .
  • each R 7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH.
  • Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl;
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and - OP(OR 7 )O-;
  • R 2 is C1 alkyl substituted with -OH or -OC(O)CH3;
  • R 3 is -OH or -OC(O)C
  • the compound comprises: , - 60 - Attorney Docket No.54462-77
  • the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide.
  • the oligonucleotide comprises DNA.
  • the oligonucleotide comprises RNA.
  • the oligonucleotide comprises one or more modified internucleoside linkages.
  • the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.
  • the compound binds to an asialoglycoprotein receptor.
  • the compound targets a hepatocyte.
  • J is the oligonucleotide: - 65 - Attorney Docket No.54462-772.601 include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: .
  • J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: - 66 - Attorney Docket No.54462-772.601 include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J is the oligonucleotide: - 68 - Attorney Docket No.54462-772.601 .
  • J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: . may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: - 69 - Attorney Docket No.54462-772.601 .
  • the structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide: - 70 - Attorney Docket No.54462-772.601 [00157] Some embodiments include the following, where the phosphate or “5’” indicates a connection [00158] Some embodiments include the following, where J is the oligonucleotide: include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: - 71 - Attorney Docket No.54462-772.601 .
  • the structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety.
  • the GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below.
  • oligonucleotide represented by Formula (III), (IV), Formula III, - 72 - Attorney Docket No.54462-772.601 Formula V, or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; - 73 - Attorney Docket No.54462-772.601 x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20; Q is selected from: C 3-20 cyclic, heterocyclic or acyclic link
  • J is an oligonucleotide: - 74 - Attorney Docket No.54462-772.601
  • L96 The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: - 75 - Attorney Docket No.54462-772.601 .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides: - 76 - Attorney Docket No.54462-772.601 [00168]
  • the structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide.
  • 2-4 GalNAc moieties are attached to the oligonucleotide.
  • J and K are oligonucleotides
  • J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphate linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • - 77 Attorney Docket No.54462-772.601
  • R is an oligonucleotide: - 78 - Attorney Docket No.54462-772.601 - 79 - Attorney Docket No.54462-772.601 or - 80 - Attorney Docket No.54462-772.601 .
  • R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • R in some instances comprises one or more phosphates linking to the oligonucleotide.
  • R in some instances comprises a phosphate linking to the oligonucleotide.
  • R in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • R in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J is an oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • - 81 - Attorney Docket No.54462-772.601 Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • [00173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more - 82 - Attorney Docket No.54462-772.601 phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J or K comprises an oligonucleotide: [00175]
  • the structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties.
  • 2-4 GalNAc moieties are attached oligonucleotide.
  • J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphate linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J is an oligonucleotide: - 83 - Attorney Docket No.54462-772.601 .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • the composition comprises an oligonucleotide that inhibits or reduces the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5’- NfsnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3.
  • the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnN- moiety-3’.
  • the sense strand comprises modification pattern 5S: 5’- nsnsnnNfnNfNfNfnnnnnnnsnsnN-moiety-3’.
  • the moiety in modification pattern 4S or 5S is a lipophilic moiety.
  • the moiety in modification pattern 4S or 5S is a lipid moiety.
  • the sense strand comprises modification pattern 6S: 5’- NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’.
  • the sense strand comprises modification pattern 7S: 5’-nsnsnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfnnnnnnnnnsnsn-3’. In some - 84 - Attorney Docket No.54462-772.601 embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfnnnnnnnnnsn- 3’.
  • the sense strand comprises modification pattern 10S: 5’- NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 11S: 5’-nsnsNfnNfnNfnNfnNfnnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’-NfsnsNfnNfnNfnNfnNfnNfnnnNfnNfnNfsn-3’.
  • the sense strand comprises modification pattern 13S: 5’- nsnsnnnnNfnNfnNfnNfnNfnNfnNfsn-3’. In some embodiments, the sense strand comprises modification pattern 14S: 5’-snnnnnnNfNfNfnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 15S: 5’-snnnnNfNfNfNfnnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 16S: 5’- snnnnNfnNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 17S: 5’-snnnnnNfNfnNfnnnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 18S: 5’-snnnnnnNfnNfNfnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 19S: 5’-snnnnNfnNfnNfnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfnNfnnnnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 21S: 5’-snnnnNfNfnnnNfNfnnnnnnnnnnsn- 3’.
  • the sense strand comprises modification pattern 22S: 5’- snnnnNfnnNfNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 23S: 5’-snnnnnNfnNfNfnnnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 24S: 5’-snnnnnnNfNfNfNfnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 25S: 5’-snnnnnNfNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNfNfNfnnnnnnnnnnnsn- 3’. In some embodiments, the sense strand comprises modification pattern 27S: 5’- snnnnnnNfNfnNfnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 28S: 5’-snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’-snnnnnnnNfnNfnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 30S: 5’-snnnnNfNfnnNfnNfnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 31S: 5’-snnnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 32S: 5’- snnnnnnNfNfdNNfnnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 33S: 5’-snnnnNfnNfnNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 34S: 5’-snnnnNfnNfNfdNNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S: 5’-snnnnnnNfNfNfnNfnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 36S: 5’- snnnnnNfNfNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 37S: 5’-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S: 5’-snnnnNfnNfNfnnnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 39S: 5’-snnnnNfnNfNfdNnnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 40S: 5’- - 85 - Attorney Docket No.54462-772.601 snnnnNfnNfNfdNnNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 41S: 5’-snnnnnnnnNfNfnnnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 42S: 5’-snnnnNfnNfNfdNnNfnnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 43S: 5’-snnnnnnNfnNfnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S: 5’-snnnnNfnNfNfNfnnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 45S: 5’-snnnnnNfnnNfNfnnnnnnnnnnsn- 3'.
  • the sense strand comprises modification pattern 46S: 5’- snnnnnnNfNfNfNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S: 5’-snnnnnNfNfnNfnnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 48S: 5’-nnNfnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3'.
  • the sense strand comprises modification pattern 49S: 5’-NfnNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 50S: 5’- nnnnnNfNfNfNfnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 51S: 5’-nnnNfNfNfNfNfnnnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 58S: 5’- nnnnmnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S: 5’-snsnnnnNfNfNfNfnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 60S: 5’-snnnnmnnNfNfNfNfnnnmnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 61S: 5’-snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62S: 5’- snnnnmnNfNfNfNfnnnmnnnninsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63S: 5’-snnnnmnNfNfNfNfnnnmnnnnsnsn-3'.
  • the sense strand comprises modification pattern 64S: 5’-nnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S: 5’-nsnsnnmnN(C16)NfNfNfnnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66S: 5'- nnnnnnNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 67S: 5'-nnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'-nnnnnnnNfNfnNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'-nnnnNfnnNfnNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 70S: 5'-nnnnnNfnNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 74S: 5'-nnnnNfNfnnNfnnnnnnnnnnsnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'-nnnnNfnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'-nnnnNfNfnnNfnNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnNfnNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 84S: 5'- nnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 85S: 5'-nnnnNfNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 86S: 5'-nnnnnnNfNfNfNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 87S: 5'-nnnnnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'-nnnnnnNfNfNfNfnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 89S: 5'-nnnnnNfnnNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 90S: 5'- nnnnnNfnNfNfNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 91S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 92S: 5'-nnnnNfnnnNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 96S: 5'- nnnnNfNfnnNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 97S: 5'-nnnnnnnNfNfnnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 98S: 5'-nnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 99S: 5'-nnnnnnnNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 100S: 5'-nnnnNfnNfNfdNnNfnnnnnnnsnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 101S: 5'- nnnnNfnNfNfdNnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfnNfNfdNnnnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 103S: 5'-snnnnnNfnNfNfnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 104S: 5'-snnnnNfNfnnNfnnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: 5'- - 87 - Attorney Docket No.54462-772.601 snnnnNfnnNfNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 106S: 5'-snnnnNfnnNfNfnnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’-snNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’.
  • the sense strand comprises modification pattern 109S: 5’- snnnnnmNfNfNfNfnnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNfNfnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 111S: 5’-NfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’.
  • the sense strand comprises modification pattern 112S: 5’-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsn-3’. In some embodiments, the sense strand comprises modification pattern 113S: 5’- nnnnnNfnNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 114S: 5’-snnnnmnNfNfNfNfnnmnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 115S: 5’-nNfnNfnNfnNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 116S: 5’-snnnnnNfnnNfnNfnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 117S: 5’- snnnnNfNfdNnnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 118S: 5’-snnnnNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 119S: 5’-snnnnNfnnnNfnNfnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 120S: 5’-snnnnnNfNfnNfNfnnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 121S: 5’- nsnsnnnnNfnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 122S: 5’-nsnsnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 123S: 5’-nsnsnnnNfNfnNfnnnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 124S: 5’-nsnsnnnNfNfnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 125S: 5’- nsnsnnNfnnnNfnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 126S: 5’-nsnsnnNfnNfnNfnNfnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 127S: 5’-nsnsnnNfNfnnNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 128S: 5’-nsnsnnnnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 129S: 5’-nsnsnnnnnNfNfnnnnnnnnnnsn- 3’.
  • the sense strand comprises modification pattern 130S: 5’- nsnsnnnNfnnNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 131S: 5’-nsnsnnNfnnnNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 132S: 5’-nsnsnnNfNfnnNfNfnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 133S: 5’-nsnsnnnnnNfNfnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 134S: 5’- nsnsnnnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 135S: 5’-nsnsnnnNfnNfNfnNfnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 136S: 5’-nsnsnnnNfNfNfnNfnnnnnnnsnsn-3’. In some embodiments, - 88 - Attorney Docket No.54462-772.601 the sense strand comprises modification pattern 137S: 5’-nsnsnnNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 138S: 5’- nsnsnnNfnnNfNfnNfnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 139S: 5’-nsnsnnNfNfnnNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 140S: 5’-nsnsnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 141S: 5’-nsnsnnnnNfnNfnnnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 142S: 5’-nsnsnnnNfnnNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 143S: 5’- nsnsnnnnnNfNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 144S: 5’-nsnsnnnnNfnNfNfnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 145S: 5’-nsnsnnnnNfNfNfNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 146S: 5’-nsnsnnnNfnNfNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 147S: 5’- nsnsnnnNfNfNfNfnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 148S: 5’-nsnsnnNfnnNfNfNfNfnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 149S: 5’-nsnsnnnNfNfnNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 150S: 5’-nsnsnnNfnNfnNfNfnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 151S: 5’- nsnsnnNfnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 152S: 5’-snnnnnNfNfNfnnnnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 153S: 5’-snnnnNfndNnNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 154S: 5’-snnnnmNfnNfNfNfnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 155S: 5’- snnnnmNfnNfNfNfNfnnnmnnnnnnsn-3'.
  • Nf is a 2’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • dN is a 2’-deoxy-modified nucleoside or a 2’-deoxy nucleoside
  • nm is a 2’-O-methoxyethyl modified nucleoside
  • i is an inosine
  • ni is a 2’-O-methyl inosine nucleoside
  • N(C16) is 2’-O-hexadecate modification and N comprises one or more nucleosides.
  • N(C16) is a 2'-O-hexadecyl adenylate.
  • the composition comprises an oligonucleotide that inhibits or reduces the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5’- nsNfsnNfnNfnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’- nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3’.
  • the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnnnsnsn-3’. In some - 89 - Attorney Docket No.54462-772.601 embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 8AS: 5’-nsNfsnnnnnnnnnnnnnnnsnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 11AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13AS: 5'- nsNfsnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-nsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS: 5'- nsNfsnnnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 17AS: 5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnnNfnnNfnnNfnNfnNfnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'- nsNfsnnnnNfnnNfnNfnNfnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 20AS: 5'-nsNfsnnnnNfnNfnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnnNfnNfnnnnNfnNfnNfnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS: 5'- nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 23AS: 5'-VPnsNfsnnnNfnNfnnnnnNfnNfnnnsnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 24AS: 5'-VPnsNfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 25AS: 5'- VPnsNfsnnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 26AS: 5'-VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-VPnsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'- nsNfsnnNfnNfnnNfnnnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 29AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 31AS: 5'- nsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'.
  • the sense strand comprises modification pattern 32AS: 5'-nsNfsnnnNfNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3'.
  • the sense strand comprises modification pattern 35AS: 5'-nsNfsnnnNfNfnnNfnnnNfnnnsnsnsn-3'.
  • the sense - 90 - Attorney Docket No.54462-772.601 strand comprises modification pattern 36AS: 5'-nsNfsnnnnNfNfnNfnnnNfnNfnnnsnsn-3'.
  • the sense strand comprises modification pattern 37AS: 5'- nsNfsnnNfn[NUNA]nnNfnnnNfnNfnnnsnsn-3'.
  • the sense strand comprises modification pattern 38AS: 5'-nsNfsnnNf[NUNA]NfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40AS: 5'- 5VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnnnsnsn-3'.
  • the antisense strand comprises modification pattern 41AS: 5'-nnnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43AS: 5'- nsNfsnnnNfNfnnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the antisense strand comprises modification pattern 44AS: 5'-nsNfsnnnNfnnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 45AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfnnNfnnnNfnNfnnnsnsn-3'.
  • the antisense strand comprises modification pattern 47AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 48AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 49AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnNfnsnsn-3'.
  • the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 51AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfnNf[UNA]NfnNfnNfnNfnNfnnnsnsn-3'.
  • the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55AS: 5'- nsNfsnnn[UNA]NfnnnNfnNfnNfnnnsnsn-3'.
  • the antisense strand comprises modification pattern 56AS: 5’-nsnsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 57AS: 5’ ⁇ nsNfsnNfnnNfnnNfnNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’ ⁇ nsNfsnnnNfnNfnNfnNfnNfnnnnnnsnsn-3’.
  • the antisense strand comprises modification pattern 59AS: 5’ ⁇ nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3’.
  • the sense strand comprises modification pattern 60AS: 5'-nsNfsnNfnNfnnNfnnnnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 61AS: 5'- nsNfsnNfnNfnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 62AS: 5'-nsNfsnNfnnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63AS: 5'-nsNfsnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64AS: 5'- nsNfsnNfnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises - 91 - Attorney Docket No.54462-772.601 modification pattern 65AS: 5'-nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 66AS: 5'-nsNfsnNfnnNfnNfnnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the sense strand comprises modification pattern 67AS: 5'- nsNfsnnnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the antisense strand comprises modification pattern 68AS: 5'-nsNfsnnNfnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 69AS: 5'-nsNfsnnn[NUNA]nNfnNfnnnNfnNfnnnsn-3’.
  • Nf is a 2’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • dN is a 2’-deoxy- modified nucleoside or a 2’-deoxy nucleoside
  • nm is a 2’-O-methoxyethyl modified nucleoside
  • i is an inosine
  • ni is a 2’-O-methyl inosine nucleoside
  • N(C16) is 2’-O-hexadecate modification
  • VP is a 5'- vinyl phosphonate
  • [NUNA] is an unlocked nucleic acid
  • [UNA] is an unlocked nucleic acid and N comprises one or more nucleosides.
  • N(C16) is a 2'-O-hexadecyl adenylate.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS
  • the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, 69AS, 70AS, 71AS, or 72AS.
  • the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, - 92 - Attorney Docket No.54462-772.601 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, - 93 - Attorney Docket No.54462-772.601 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, - 94 - Attorney Docket No.54462-772.601 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, - 95 - Attorney Docket No.54462-772.601 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69
  • the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, - 96 - Attorney Docket No.54462-772.601 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, - 97 - Attorney Docket No.54462-772.601 67AS, 68AS, or
  • the sense strand comprises pattern 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the - 98 - Attorney Docket No.54462-772.601 sense strand comprises pattern 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 52S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 57S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 58S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 59S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS.
  • the sense strand comprises pattern 60S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 61S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 62S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, - 100 - Attorney Docket No.54462-772.601 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 63S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 64S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 65S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 66S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 67S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 68S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 69S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, - 101 - Attorney Docket No.54462-772.601 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 70S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 71S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 72S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 73S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 74S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 75S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 76S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, - 102 - Attorney Docket No.54462-772.601 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 77S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 78S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 79S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 80S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 81S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 82S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 83S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, - 103 - Attorney Docket No.54462-772.601 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 84S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 85S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 86S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 87S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 88S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 89S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 90S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, - 104 - Attorney Docket No.54462-772.601 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 91S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 92S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 93S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 94S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 95S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 96S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 97S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, - 105 - Attorney Docket No.54462-772.601 67AS, 68AS, or
  • the sense strand comprises pattern 98S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 99S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 100S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 101S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 102S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 103S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 104S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or - 106 - Attorney Docket No.54462-772.601
  • the sense strand comprises pattern 105S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 106S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 107S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 108S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 109S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 110S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 111S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 112S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 113S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 114S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 115S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 116S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 117S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 118S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the - 108 - Attorney Docket No.54462-772.601 sense strand comprises pattern 119S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 120S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 121S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 122S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 123S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 124S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 125S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense - 109 - Attorney Docket No.54462-772.601 strand comprises pattern 126S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 127S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 128S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 129S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 130S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 131S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 132S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand - 110 - Attorney Docket No.54462-772.601 comprises pattern 133S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 134S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 135S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 136S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 137S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 138S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 139S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises - 111 - Attorney Docket No.54462-772.601 pattern 140S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or
  • the sense strand comprises pattern 141S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 142S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 143S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 144S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 145S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 146S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 148S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 149S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 150S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 151S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 152S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 153S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 155S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, - 115 - Attorney Docket No.54462-772.601 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S.34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, - 116 - Attorney Docket No.54462-772.601 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand - 120 - Attorney Docket No.54462-772.601 comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S,
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, - 121 - Attorney Docket No.54462-772.601 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, - 122 - Attorney Docket No.54462-772.601 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, - 126 - Attorney Docket No.54462-772.601 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, - 127 - Attorney Docket No.54462-772.601 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, - 128 - Attorney Docket No.54462-772.601 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, - 129 - Attorney Docket No.54462-772.601 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76
  • the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, or 9S.
  • the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S,
  • the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS.
  • the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS
  • the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S,
  • the sense strand or the antisense strand comprises modification pattern ASO1In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O- - 131 - Attorney Docket No.54462-772.601 methyl modified pyrimidines.
  • all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise 2’-fluoro modified purines.
  • all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines.
  • all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O- methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2’-fluoro modified purines. [00195] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • all purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. - 132 - Attorney Docket No.54462-772.601 [00196] In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines.
  • pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines.
  • purines of the antisense strand comprise 2’-O-methyl modified purines
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines
  • purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines
  • purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O- methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines. [00198] In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines.
  • all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines.
  • all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines
  • all purines of the antisense strand comprise 2’-fluoro modified purines.
  • the modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency.
  • the siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject.
  • the modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.
  • the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs.
  • the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand.
  • One strand (antisense strand) is complementary to a PLOD2 mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate.
  • the oligonucleotide is used to knock down a PLOD2 mRNA or a target protein.
  • the sense strand has the same sequence as the PLOD2 mRNA.
  • the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern.
  • position 9 counting from the 5’ end of the sense strand may have a 2’F modification.
  • position 9 of the sense strand is a pyrimidine
  • all purines in the sense strand have a 2’OMe modification.
  • position 9 is the only pyrimidine between positions 5 and 11 of the sense stand
  • position 9 is the only position with a 2’F modification in the sense strand.
  • position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines
  • both of these pyrimidines are the only two positions with a 2’F modification in the sense strand.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.
  • Terminal modifications useful for modulating activity include modification of the 5' end of the antisense strand with phosphate or phosphate analogs.
  • the 5' end of the antisense strand is phosphorylated or includes a phosphoryl analog.
  • Exemplary 5'-phosphate modifications include those which are compatible with RNA-induced silencing complex (RISC) mediated gene silencing.
  • the 3' end of the antisense strand is phosphorylated or includes a phosphoryl analog.
  • the 5' end of the sense strand is phosphorylated or includes a phosphoryl analog.
  • the 3' end of the sense strand is phosphorylated or includes a phosphoryl analog.
  • the oligonucleotide comprises a phosphate or phosphate mimic at the 5’ end of the antisense strand.
  • the phosphate mimic includes a 5'-vinyl phosphonate (VP). In some embodiment, the phosphate mimic is a 5'-VP. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3' end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 5' end of the sense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3' end of the sense strand. [00206] In some embodiments, the sense strand comprises or consists of RNA or modified RNA nucleotides.
  • the sense strand comprises a deoxy nucleoside.
  • the deoxy nucleoside may include a DNA nucleoside.
  • the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside.
  • the deoxy nucleoside may be at a position within the sense strand (5’ to 3’, where the 5’ position is 1).
  • the position within the sense strand may be or include position 2, 4, 6, 8, 9, 10, 12, 14, 16, or 18, or a combination of said positions.
  • the position within the sense strand may be or include position 2, 4, 6, 8, 10, 12, 14, 16, or 18, or a combination of said positions.
  • the position within the sense strand may be or include position 2, 6, 9, 10, 14, or 18, or a combination of said positions.
  • the position within the sense strand may be or include position 2, 6, 10, 14, or 18, or a combination of said positions.
  • the position within the sense strand may be or include position 4, 8, 9, 12, or 16, or a combination of said positions.
  • the position within the sense strand may be or include position 4, 8, 12, or 16, or a combination of said positions.
  • the position within the sense strand may include position 9.
  • the position within the sense strand may be position 9.
  • the sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, - 135 - Attorney Docket No.54462-772.601 16, 17, 18, or 19 deoxy nucleosides.
  • the sense strand includes 1 deoxy nucleoside.
  • the sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides.
  • the sense strand may include deoxy nucleosides at all even positions.
  • the sense strand may include deoxy nucleosides at some even positions.
  • the sense strand may include deoxy nucleosides at every other even position.
  • the sense strand may include 1 deoxy nucleoside.
  • the sense strand may include at least 1 deoxy nucleoside.
  • the sense strand may include at least 2 deoxy nucleosides.
  • the sense strand may include at least 3 deoxy nucleosides.
  • the sense strand may include at least 4 deoxy nucleosides.
  • the sense strand may include at least 5 deoxy nucleosides.
  • the sense strand may include at least 6 deoxy nucleosides.
  • the sense strand may include at least 7 deoxy nucleosides.
  • the sense strand may include at least 8 deoxy nucleosides.
  • the sense strand may include at least 9 deoxy nucleosides.
  • the sense strand may include at least 10 deoxy nucleosides.
  • the sense strand may include no greater than 2 deoxy nucleosides.
  • the sense strand may include no greater than 3 deoxy nucleosides.
  • the sense strand may include no greater than 4 deoxy nucleosides.
  • the sense strand may include no greater than 5 deoxy nucleosides.
  • the sense strand may include no greater than 6 deoxy nucleosides.
  • the sense strand may include no greater than 7 deoxy nucleosides.
  • the sense strand may include no greater than 8 deoxy nucleosides.
  • the sense strand may include no greater than 9 deoxy nucleosides.
  • the sense strand may include no greater than 10 deoxy nucleosides.
  • the antisense strand comprises or consists of RNA or modified RNA nucleotides.
  • the antisense strand comprises a deoxy nucleoside.
  • the deoxy nucleoside may include a DNA nucleoside.
  • the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside.
  • the antisense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides.
  • nucleosides at positions 1-8 include a mixture of 2’-fluoro and 2’- O-methyl modified nucleosides.
  • purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides.
  • pyrimidines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides.
  • nucleosides at positions 1-8 all include 2’-O-methyl modified nucleosides.
  • purines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides.
  • pyrimidines at positions - 136 - Attorney Docket No.54462-772.601 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and purines at positions 1-8 all include 2’-O-methyl modified nucleosides.
  • compositions comprising an oligonucleotide that targets PLOD2 and when administered to a cell decreases expression of PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one internucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleo
  • the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand.
  • any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyr
  • any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidine
  • the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (i
  • any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines
  • a deoxy nucleoside may be included in the sense strand.
  • the sense strand includes the deoxy nucleoside.
  • the deoxy nucleoside may be at nucleoside position 9 of the sense strand.
  • the sense strand does not include a deoxy nucleoside.
  • the deoxy nucleoside of the sense strand may be otherwise unmodified.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 4.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 4.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 80% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 85% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 90% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or at least 95% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2.
  • the sense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7464- 7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2.
  • the sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.
  • the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NOS: 7774-8083 in PLOD2, at least 80% identical to SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, at least 85% identical to SEQ ID NOS: 7774-8083 in PLOD2, at least 90% identical to SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178- 8181, or 8192-8193 in PLOD2, or at least 95% identical to SEQ ID NOS: 7774-8083,8107-8111, 8150- 8159, 8178-8181, or 8192-8193 in PLOD2.
  • the antisense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or - 140 - Attorney Docket No.54462-772.601 consists of the sequence of SEQ ID NOS: 7774-8083,8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, or an antisense strand sequence thereof having
  • the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOS: 7774-8083,8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2.
  • the antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.
  • the antisense strand may comprise a 5'-vinyl phosphonate (VP).
  • VP 5'-vinyl phosphonate
  • the sense strand or antisense strand may comprise a moiety such as a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand.
  • LRP lipoprotein receptor related protein
  • TfR transferrin receptor
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA.
  • the GalNAc moiety is ETL17.
  • lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) or integrin alpha-v-beta-3 or arginine- glycine-aspartic acid (RGD) peptide.
  • the siRNA may comprises the sense strand and/or the antisense strand sequence of an siRNA in any table included herein that includes modifications; or may include a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; or may include a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • NEP non-human primate
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset G. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset G.
  • any of the aforementioned siRNAs may include a sense strand of subset G, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A.
  • Any of the aforementioned siRNAs may include an antisense strand of one of subset G, wherein the nucleotide at the 5’ end of the sense strand - 141 - Attorney Docket No.54462-772.601 sequence has been modified to a T.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G.
  • any of the aforementioned siRNA comprising a sense strand or antisense stand comprises a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense or anti sense strand sequence of one of subset G.
  • the sense strand or antisense stand may comprise a lipid moiety.
  • the sense or antisense strand may comprise a GalNAc moiety.
  • the sense strand or antisense stand may comprise an integrin or an integrin targeting ligand.
  • the sense strand or antisense stand may comprise an angiopep-2.
  • the sense strand or antisense stand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • the antisense strand may comprise a glucose transporter protein.
  • the sense strand or antisense stand may comprise an LDL receptor ligand.
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA.
  • the GalNAc moiety is ETL17.
  • lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 ETL28, ETL29, ETL31 or ETL32.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 ( ⁇ v ⁇ 6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • the sense strand of any of the siRNAs of subset G comprises siRNA with a particular modification pattern. In this modification pattern, position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification. If position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand.
  • both of these pyrimidines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • both of these purines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.
  • position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand.
  • the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl.
  • each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications.
  • each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof.
  • the oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.
  • the sense strand comprises purines and pyrimidines.
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl.
  • all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- - 143 - Attorney Docket No.54462-772.601 methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl.
  • all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl.
  • the sense strand may include a 2’ deoxy nucleoside.
  • at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside.
  • at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside.
  • At least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside.
  • At least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro.
  • all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. 4.
  • the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3’, wherein “dN” is any - 144 - Attorney Docket No.54462-772.601 deoxynucleotide, “n” is a 2’-O-methyl or 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate linkage.
  • the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77
  • the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. [00228] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome.
  • the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof.
  • the oligonucleotide is combined with lipids, nanoparticles, polymers, liposomes, micelles, or another delivery system.
  • the composition is formulated for delivery to a subject’s osteoarthritic joint (i.e., intra-articularly).
  • the composition is formulated administration to the joint via topical, transdermal, intradermal, or subcutaneous route.
  • E. Kits [00230] Described herein, in some embodiments, are kits.
  • the kit may include an oligonucleotide such as an siRNA described herein.
  • the oligonucleotide may be conjugated to a lipid moiety or to a sugar moiety.
  • the kit may include a lipid moiety.
  • the kit may include a sugar moiety.
  • the oligonucleotide may comprise nucleoside modifications or modified internucleoside linkages.
  • the oligonucleotide may include any modifications described herein, such as modifications from a base sequence.
  • the kit may include a delivery reagent such as a needle.
  • the kit may comprise a container.
  • kits may comprise an oligonucleotide such as an siRNA described herein within a pharmaceutically acceptable carrier or - 145 - Attorney Docket No.54462-772.601 diluent.
  • the kits may further comprise excipients.
  • the kit may include instructions for use, such as methods for use in a method described herein. II. METHODS AND USES [00231] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject. [00232] Some embodiments relate to a method of treating a disorder in a subject in need thereof.
  • Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject. [00233] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder.
  • the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject. [00234] Some embodiments relate to a method of preventing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject. [00235] Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof.
  • Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject. [00236] Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.
  • a pharmaceutical composition described herein is carried out by any of the many known routes of administration, including intravenously, intra-arterially, subcutaneously, intra- peritoneally or intra-cerebrally, as determined by a skilled practitioner. Using specialized formulations, it is possible to administer the compositions orally or via inhalation or via intranasal instillation.
  • a compound of the present invention is formulated for topical administration, including as eardrops, eye drops, dermal formulation, transdermal formulation and the like.
  • the administration is systemic. In some embodiments, the administration is intravenous.
  • the administration is by injection. In some embodiments, the administration is to a subject’s osteoarthritic joint. In some embodiments, the administration is intra-articularly. In some embodiments, the administration to the joint is topical, transdermal, intradermal, or subcutaneous route. Administration of the compositions and compounds provided herein can be via any of the accepted modes of administration including, but not limited to, subcutaneous, intravenous, topical, transdermal, intraperitoneal, intramuscular, intrathecal, intra-articular, intracapsular, intraspinal, intrasynovial, epidural, intravascular, or via irrigation of infected bone. In some embodiments, administration is parenteral. In some embodiments, administration is intraarticular.
  • the compositions provided herein are administered parenterally, including intramuscularly, intra-articularly, periarticularly, intraspinally, intrasynovially, and epidurally.
  • the compositions can be injected locally at the site of the osteoarthritis (e.g., knee, hip, shoulder, etc.). Injections can occur at one or more locations surrounding the joint.
  • the injection is guided using an imaging method such as ultrasound.
  • administration e.g., injection
  • disorders include treating a disorder in a subject in need thereof.
  • the disorder includes an inflammatory disorder.
  • the disorder is an arthropathy.
  • the arthropathy includes an osteoarthritis.
  • arthropathy leads to arthroplasty, arthroplasty of the hip, arthroplasty of the knee.
  • the disorder includes a temporomandibular joint (TMJ) disorders.
  • the disorder includes an arthroplasty.
  • the disorder includes an arthrosis.
  • the disorder includes an arthralgia.
  • the disorder includes a degenerative joint disease.
  • the disorder includes degradation and/or disruption of cartilage homeostasis.
  • the cartilage homeostasis includes osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, achondroplasia, Paget's disease, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amyloidosis, hydrarthrosis, periodical disease, rheumatoid spondylitis, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
  • the subject is a vertebrate.
  • the subject is an animal.
  • the subject is a mammal.
  • the subject is a dog.
  • the subject is a cat.
  • the subject is a cattle.
  • the subject is a mouse.
  • the subject is a rat.
  • the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old).
  • the subject has a body mass index (BMI) of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers.
  • BMI body mass index
  • the subject is overweight.
  • the subject has a BMI of 25 or more.
  • the subject has a BMI of 25-29.
  • the subject is obese.
  • the subject has a BMI of 30 or more.
  • the subject has a BMI of 30-39.
  • the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 15-50. [00243] In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is > 90 years of age. In some embodiments, the subject is > 85 years of age. In some embodiments, the subject is > 80 years of age. In some embodiments, the subject is > 70 years of age. In some embodiments, the subject is > 60 years of age. In some embodiments, the subject is > 50 years of age. In some embodiments, the subject is > 40 years of age. In some embodiments, the subject is > 30 years of age. In some embodiments, the subject is > 20 years of age.
  • the subject is > 10 years of age. In some embodiments, the subject is > 1 years of age. In some embodiments, the subject is > 0 years of age. [00244] In some embodiments, the subject is ⁇ 100 years of age. In some embodiments, the subject is ⁇ 90 years of age. In some embodiments, the subject is ⁇ 85 years of age. In some embodiments, the subject is ⁇ 80 years of age. In some embodiments, the subject is ⁇ 70 years of age. In some embodiments, the subject is ⁇ 60 years of age. In some embodiments, the subject is ⁇ 50 years of age. In some embodiments, the subject is ⁇ 40 years of age. In some embodiments, the subject is ⁇ 30 years of age.
  • the subject is ⁇ 20 years of age. In some embodiments, the subject is ⁇ 10 years of age. In some embodiments, the subject is ⁇ 1 years of age. [00245] In some embodiments, the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age. - 148 - Attorney Docket No.54462-772.601 [00246] The subject may have a disorder described herein. The subject may have inflammation.
  • the subject may have an inflammatory disease.
  • the subject may have an arthropathy or an osteoarthritis.
  • H. Baseline measurements Some embodiments of the methods described herein include obtaining a baseline measurement from a subject.
  • a baseline measurement is obtained from the subject prior to treating the subject.
  • Non-limiting examples of baseline measurements include a baseline joint function measurement, joint structure measurement, pain measurement, inflammation markers measurement, cartilage biomarkers measurement, bone biomarkers measurement, synovial biomarkers measurement, patient-reported outcome measurement (PROMs), physical function measurement, Quality of life assessment measurement, osteoarthritis flare-up measurement, or a radiographic progression measurement.
  • the baseline measurement is obtained directly from the subject.
  • the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. [00249] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • an immunoassay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • the baseline measurement is obtained by PCR.
  • the baseline measurement is a joint function measurement. Examples of baseline joint function measurement may include a measurement of range of motion, morning stiffness duration and grip strength.
  • the baseline measurement is a joint structure measurement. Examples of baseline joint structure measurement may include a measurement of joint space narrowing, osteophyte formation, subchondral sclerosis, subchondral cyst. Joint space narrowing (JSN) is typically graded using the Osteoarthritis Research Society International (OARSI) atlas criteria, or the Kellgren and Lawrence (K/L) system.
  • OFSI Osteoarthritis Research Society International
  • K/L Kellgren and Lawrence
  • the OARSI atlas criteria grades JSN using a 0-3 scale with Grade 0 indicating an absence of JSN, and Grades 1, 2 and 3 indicating mild, moderate, and severe JSN (Altman and Gold, Osteoarthritis Cartilage 2007; 15(Suppl A):A1-A56).
  • the K/L system grades JSN using a 0-4 scale with Grade 0 indicating an absence of JSN, Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 indicating minimal, moderate, and severe JSN (Kellgren and Lawrence, Ann Rheum Dis 1957; 16:494-502). Based on these criteria, OARSI Grade 0 (absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtful presence of JSN).
  • the baseline measurement is a pain measurement assessed by visual analogue scale (VAS) and WOMAC pain subscale.
  • VAS visual analogue scale
  • NRS numerical rating scale
  • VAS and NRS scores have been shown to be strongly correlated (slope of regression line, 1.01), indicating that a score on the 10-cm VAS is equivalent to the same score on 10-point NRS (Bijur P E et al. Acad Emerg Med 2003; 10:390-392).
  • a VAS score of 5 cm (or 50 mm) is equivalent to an NRS score of 5.
  • Knee pain in a person with a VAS score of 5 cm or 50 mm or higher, or an NRS score of 5 or higher, may be referred to herein as moderate to severe knee pain.
  • the person has baseline pain intensity of 5 or greater measured using the 0-10 numerical rating scale (NRS), or 50 mm or greater using the 100 mm visual analog scale (VAS).
  • the person being treated for pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, joint space narrowing.
  • the baseline measurement includes an inflammation measurement.
  • the baseline measurement includes a measurement of inflammation markers. Examples of inflammation markers measurement may include measuring C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1 ⁇ , tumor necrosis factor (TNF)- ⁇ , or IL-6.
  • the baseline measurement includes a measurement of cartilage biomarkers.
  • cartilage biomarkers measurement may include measuring COMP, aggrecan, type II collagen, proteoglycans, or Hyaluronic acid.
  • the baseline measurement includes a measurement of bone biomarkers. Examples of bone biomarkers measurement may include measuring CTX-II, NTX-I.
  • the baseline measurement includes a measurement of synovial biomarkers. Examples of synovial biomarkers measurement may include measuring MMPs, ADAMTS, and the number of pyridinoline cross-links per triple helix collagen.
  • the baseline measurement includes patient-reported outcome measures (PROMs) including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
  • PROMs patient-reported outcome measures
  • WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
  • the baseline measurement includes physical function measurement. Examples of physical function measurement may include 6-minute walk test, timed up-and-go test.
  • the baseline measurement includes quality of life assessments. Examples of quality of life assessments may include SF-36, EQ-5D).
  • the baseline measurement includes osteoarthritis exacerbations measurement.
  • the baseline measurement includes radiographic progression measurement assessed by Kellgren-Lawrence grading scale.
  • the baseline measurement is a baseline PLOD2 protein measurement.
  • the baseline PLOD2 protein measurement comprises a baseline PLOD2 protein level. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample weight. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample volume. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per total protein within the - 150 - Attorney Docket No.54462-772.601 sample. In some embodiments, the baseline PLOD2 protein measurement is a baseline circulating PLOD2 protein measurement.
  • the baseline PLOD2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline PLOD2 mRNA measurement.
  • the baseline PLOD2 mRNA measurement comprises a baseline PLOD2 mRNA level.
  • the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD23 mRNA per sample weight.
  • the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample volume.
  • the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total mRNA within the sample. In some embodiments, the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total nucleic acids within the sample. In some embodiments, the baseline PLOD2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline PLOD2 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR).
  • PCR polymerase chain reaction
  • the PCR comprises reverse transcription of the PLOD2 mRNA.
  • Some embodiments of the methods described herein include obtaining a sample from a subject.
  • the baseline measurement is obtained in a sample obtained from the subject.
  • the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein.
  • a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.
  • the sample comprises a fluid.
  • the sample is a fluid sample.
  • the baseline PLOD2 protein measurement may be obtained in a fluid sample obtained from the patient.
  • the baseline PLOD2 mRNA measurement is obtained in a fluid sample.
  • the sample is a blood, plasma, or serum sample.
  • the sample comprises blood.
  • the sample is a blood sample.
  • the sample is a whole-blood sample.
  • the sample comprises plasma.
  • the sample is a plasma sample.
  • a blood sample may be a plasma sample.
  • the sample comprises serum.
  • the sample is a serum sample.
  • the fluid sample includes a synovial fluid sample.
  • the sample is fractionated or centrifuged.
  • the sample comprises a tissue.
  • the sample is a tissue sample.
  • the tissue comprises articular joint, articular cartilage, synovium, synovial membrane.
  • the baseline PLOD2 mRNA measurement, or the baseline PLOD2 protein measurement may be obtained in a articular joint, articular cartilage, synovium, synovial membrane sample obtained from the patient. - 151 - Attorney Docket No.54462-772.601 [00260]
  • the sample includes cells.
  • the sample comprises a cell.
  • the cell is a chondrocyte.
  • the cell is a osteoblast.
  • the cell is a synoviocyte. In some embodiments, the cell is a fibroblast.
  • the composition or administration of the composition affects a measurement such as osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, Temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, a PLOD2 protein measurement (for example, circulating or tissue PLOD2 protein levels), or a PLOD2 mRNA measurement, relative to the baseline measurement.
  • TMJ Temporomandibular joint
  • Some embodiments of the methods described herein include obtaining the measurement from a subject.
  • the measurement may be obtained from the subject after treating the subject.
  • the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject.
  • the measurement is an indication that the disorder has been treated.
  • the measurement is obtained directly from the subject.
  • the measurement is obtained noninvasively using an imaging device.
  • the measurement is obtained in a second sample from the subject.
  • the measurement is obtained in one or more histological tissue sections.
  • the measurement is obtained by performing an assay on the second sample obtained from the subject.
  • the measurement is obtained by an assay, such as an assay described herein.
  • the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay.
  • the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • the measurement is obtained by PCR.
  • the measurement is obtained by histology.
  • the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample. [00264] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition.
  • the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the - 152 - Attorney Docket No.54462-772.601 composition.
  • the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.
  • the composition improves or reduces the measurement relative to the baseline measurement. For example, an adverse phenotype of an arthropathy may be improved or reduced upon administration of the composition.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject.
  • the measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is reduced by no more than about 10%, relative to the baseline measurement.
  • the measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00266] In some embodiments, the composition improves or increases the measurement relative to the baseline measurement. For example, a protective phenotype of arthropathy may be improved or increased upon administration of the composition.
  • the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement.
  • the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement.
  • the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than - 153 - Attorney Docket No.54462-772.601 about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement.
  • the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a joint function measurement. Examples of joint function measurement may include a measurement of range of motion, morning stiffness duration and grip strength.
  • the composition improves the joint function measurement relative to the baseline joint function measurement. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject.
  • the joint function measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 10% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline joint function measurement.
  • the joint function measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 10%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline joint function measurement.
  • the joint function measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages. [00268] In some embodiments, the measurement is a joint structure measurement. Examples of baseline joint structure measurement may include a measurement of joint space narrowing, osteophyte formation, subchondral sclerosis, subchondral cyst.
  • JSN Joint space narrowing
  • OARSI Osteoarthritis Research Society International
  • K/L Kellgren and Lawrence
  • the OARSI atlas criteria grades JSN using a 0-3 scale with Grade 0 indicating an absence of JSN, and Grades 1, 2 and 3 indicating mild, moderate, and severe JSN (Altman and Gold, Osteoarthritis - 154 - Attorney Docket No.54462-772.601 Cartilage 2007; 15(Suppl A):A1-A56).
  • the K/L system grades JSN using a 0-4 scale with Grade 0 indicating an absence of JSN, Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 indicating minimal, moderate, and severe JSN (Kellgren and Lawrence, Ann Rheum Dis 1957; 16:494-502). Based on these criteria, OARSI Grade 0 (absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtful presence of JSN). Knee pain in a person having OARSI Grade 0 or K/L Grade or 1 JSN in the knee where the pain occurs may be referred to herein as a “normal joint space knee pain.” [00269] In some embodiments, the composition improves the joint structure measurement relative to the baseline joint structure measurement.
  • the improvement is measured directly in the subject after administering the composition to the subject.
  • the joint structure measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline joint structure measurement.
  • the joint structure measurement is improved by about 10% or more, relative to the baseline joint structure measurement.
  • the joint structure measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline joint structure measurement.
  • the joint structure measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by no more than about 10%, relative to the baseline joint structure measurement.
  • the joint structure measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline joint function measurement. In some embodiments, the joint structure measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline joint structure measurement.
  • the joint structure measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • VAS and NRS scores have been shown to be strongly correlated (slope of regression line, 1.01), indicating that a score on the 10-cm VAS is equivalent to the same score on 10-point NRS (Bijur P E et al. Acad Emerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm) is equivalent to an NRS score of 5.
  • Knee pain in a person with a VAS score of 5 - 155 - Attorney Docket No.54462-772.601 cm or 50 mm or higher, or an NRS score of 5 or higher, may be referred to herein as moderate to severe knee pain.
  • the person has baseline pain intensity of 5 or greater measured using the 0-10 numerical rating scale (NRS), or 50 mm or greater using the 100 mm visual analog scale (VAS).
  • the person being treated for pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, joint space narrowing.
  • the composition improves the pain measurement relative to the baseline pain measurement.
  • the improvement is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject. In some embodiments, the pain measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by about 10% or more, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline pain measurement.
  • the pain measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by no more than about 10%, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline pain measurement.
  • the pain measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement includes an inflammation measurement.
  • the measurement includes a measurement of inflammation markers. Examples of inflammation markers measurement may include measuring C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1 ⁇ , tumor necrosis factor (TNF)- ⁇ , or IL-6.
  • the measurement includes a measurement of cartilage biomarkers.
  • cartilage biomarkers measurement may include measuring COMP, aggrecan, type I collagen, type II Collagen, proteoglycan or Hyaluronic acid.
  • the measurement includes a measurement of bone biomarkers.
  • bone biomarkers measurement may include measuring CTX-II, NTX-I.
  • the measurement includes a measurement of synovial biomarkers.
  • synovial biomarkers measurement may include measuring MMPs, ADAMTS, and the number of pyridinoline cross-links per triple helix collagen.
  • the composition improves the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the improvement is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the inflammation marker - 156 - Attorney Docket No.54462-772.601 measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 10% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 10%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, or no more than about 80%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by any of the aforementioned percentages or ranges of percentages, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement.
  • the measurement includes patient-reported outcome measures (PROMs) including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
  • PROMs patient-reported outcome measures
  • WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
  • the measurement includes a physical function measurement. Examples of physical function measurement may include 6-minute walk test, timed up-and-go test.
  • the measurement includes quality of life assessments. Examples of quality of life assessments may include SF-36, EQ-5D).
  • the baseline measurement includes osteoarthritis flare-ups (or - 157 - Attorney Docket No.54462-772.601 exacerbations) measurement.
  • the baseline measurement includes radiographic progression measurement assessed by Kellgren-Lawrence grading scale.
  • the composition improves the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement.
  • the improvement is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject.
  • the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 10% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement.
  • patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement.
  • the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 10%, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement.
  • the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline patient- reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis - 158 - Attorney Docket No.54462-772.601 flare-ups measurement or radiographic progression measurement.
  • the patient- reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a PLOD2 protein measurement.
  • the PLOD2 protein measurement comprises a PLOD2 protein level.
  • the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample weight.
  • the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample volume.
  • the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per total protein within the sample.
  • the PLOD2 protein measurement is a circulating PLOD2 protein measurement.
  • the PLOD2 protein measurement is a synovial fluid PLOD2 protein measurement.
  • the PLOD2 protein measurement is a tissue PLOD2 protein measurement.
  • the PLOD2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. [00276]
  • the composition reduces the PLOD2 protein measurement relative to the baseline PLOD2 protein measurement.
  • the composition reduces circulating PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the composition reduces synovial fluid PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the composition reduces tissue PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the reduced PLOD2 protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a blood, serum, plasma, or synovial fluid sample. In some embodiments, the PLOD2 protein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline PLOD2 protein measurement.
  • the PLOD2 protein measurement is reduced by about 10% or more, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by no more than about 10%, relative to the baseline PLOD2 protein measurement.
  • the PLOD2 protein measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by 2.5%, 5%, 7.5%, 19%, 20%, 30%, - 159 - Attorney Docket No.54462-772.601 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00277] In some embodiments, the measurement is a PLOD2 mRNA measurement.
  • the PLOD2 mRNA measurement comprises a PLOD2 mRNA level. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample weight. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample volume. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total mRNA within the sample or first sample. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total nucleic acids within the sample.
  • the PLOD2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample.
  • the PLOD2 mRNA measurement is obtained by an assay such as a PCR assay.
  • the PCR comprises qPCR.
  • the PCR comprises reverse transcription of the PLOD2 mRNA.
  • the composition reduces the PLOD2 mRNA measurement relative to the baseline PLOD2 mRNA measurement.
  • the PLOD2 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject.
  • the composition reduces PLOD2 mRNA levels relative to the baseline PLOD2 mRNA levels.
  • the reduced PLOD2 mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject.
  • the sample is a synovial fluid sample.
  • the sample is a tissue sample.
  • the PLOD2 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline PLOD2 mRNA measurement.
  • the PLOD2 mRNA measurement is reduced by about 10% or more, relative to the baseline PLOD2 mRNA measurement.
  • the PLOD2 mRNA measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by no more than about 10%, relative to the baseline PLOD2 mRNA measurement.
  • the PLOD2 mRNA measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages. - 160 - Attorney Docket No.54462-772.601 III.
  • a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • subject and “patient” may be used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “about” a number refers to that number plus or minus 10% of that number.
  • the term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is - 161 - Attorney Docket No.54462-772.601 observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • the term “baseline” in reference to an arthropathy-related parameter refers to the value of a patient's arthropathy related parameter before or at the time of administration of a pharmaceutical composition comprising the oligonucleotide such as siRNA as described above.
  • the term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.
  • the terms “marker” or “biomarker” as used interchangeably herein refer to any molecule used as a target for analyzing test samples obtained from subjects, and encompass proteins or polypeptides themselves as well as antibodies against same that may be present in a test sample. Proteins or polypeptides used as a marker include any variants and fragments thereof, and in particular, immunologically detectable fragments. For example, it is appreciated that variants of a marker polypeptide are encoded by the same gene, but can differ in their isoelectric point or molecular weight or both as a result of alternative processing such as alternative splicing and/or differences in post- translational modification (e.g., glycosylation, acylation, and/or phosphorylation).
  • alternative processing such as alternative splicing and/or differences in post- translational modification (e.g., glycosylation, acylation, and/or phosphorylation).
  • proteins or polypeptides used as a marker according to the present disclosure include fragments thereof.
  • certain markers can be synthesized in an inactive form that is subsequently converted to an active form by proteolysis. Proteins or fragments thereof can also occur as part of a complex. Proteins or polypeptides used as markers according to the present disclosure also include such complexes.
  • biomarker and “marker” also encompass nucleic acid molecules comprising a nucleotide sequence that codes for a marker protein, and also polynucleotides that can hybridize under stringent conditions with a part of such nucleic acid molecules.
  • sample generally refers to a biological material being tested for and/or suspected of containing an analyte of interest.
  • the biological material may be derived from any biological source but preferably is a cell, tissue or biological fluid likely to contain the analyte of interest.
  • biological materials include, but are not limited to, stool, whole blood, serum, plasma, red blood cells, platelets, interstitial fluid, saliva, ocular lens fluid, cerebral spinal fluid, sweat, urine, ascites fluid, mucous, nasal fluid, sputum, synovial fluid, peritoneal fluid, - 162 - Attorney Docket No.54462-772.601 vaginal fluid chondrocytes, osteoblasts, synoviocytes, fibroblasts, articular joint, articular cartilage, synovium, synovial membrane.
  • osteoarthritis refers to the disease also known as osteoarthrosis and degenerative joint disease, characterized by inflammation and damage to, or loss of cartilage in any joint or joints, and joint pain.
  • Clinical standards for diagnosing osteoarthritis in subjects including mammalian subjects such as canines and humans are well known and include for example swelling or enlargement of joints, joint tenderness or pain, decreased range of motion in joints, visible joint deformities such as bony growths, and crepitus. Symptoms can be identified by clinical observation and history, or imaging including MRI and X-ray.
  • Criteria for diagnosing the presence or absence of OA and severity or degree of OA include but are not limited to the ACR Criteria for knee OA (R. Altman et al., Development of criteria for the classification and reporting of osteoarthritis: Classification of osteoarthritis of the knee: Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. ARTHRITIS RHEUM. August 29(8):1039-1049(1986)), functional status criteria according to WOMAC (N. Bellamy et al., 1988, Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
  • Cx-y or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C1-6alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • Cx-yalkenyl and Cx-yalkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond.
  • carbbocycle as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon.
  • Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • a bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane.
  • a bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl. - 163 - Attorney Docket No.54462-772.601 [00294]
  • aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • cycloalkyl refers to a saturated ring in which each atom of the ring is carbon.
  • Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a cycloalkyl comprises three to ten carbon atoms.
  • a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7-dimethyl bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.
  • cycloalkenyl refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons.
  • Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1- chloromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the haloalkyl radical is optionally further substituted as described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12- membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • a bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.
  • heteroaryl refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • heteroaryl radical is optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,
  • heterocycloalkyl refers to a saturated ring with carbon atoms and at least one heteroatom.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, -
  • heterocycloalkenyl refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms.
  • the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydro
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • a "derivative" polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment.
  • a derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.
  • a detectable label either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.
  • Some embodiments refer to nucleic acid sequence information. It is contemplated that in some embodiments, thymine (T) may be interchanged with uracil (U), or vice versa. For example, some sequences in the sequence listing may recite Ts, but these may be replaced with Us in some embodiments. In some oligonucleotides with nucleic acid sequences that include uracil, the uracil may be replaced with thymine.
  • oligonucleotides with nucleic acid sequences that include thymine may be replaced with uracil.
  • an oligonucleotide such as an siRNA comprises or consists of RNA.
  • the oligonucleotide may comprise or consist of DNA.
  • an ASO may include DNA.
  • Nf refers to a 2’-fluoro- modified nucleoside
  • dN e.g., dA, dC, dG, dT, or dU
  • n e.g., a, c, g, t, or u
  • s refers to a phosphorothioate linkage.
  • a pyrimidine may include cytosine (C), thymine (T), or uracil (U).
  • a pyrimidine may include C or U.
  • a pyrimidine may include C or T. Where a pyrimidine is referred to, it may indicate a nucleoside or nucleotide comprising a pyrimidine.
  • a purine may include guanine (G) or adenine (A). Where a purine is referred to, it may indicate a nucleoside or nucleotide comprising a purine. [00310]
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. - 167 - Attorney Docket No.54462-772.601 IV.
  • the PLOD2 gene burden was associated with decreased risk of osteoarthritis and osteoarthritis of the knee, and decreased risk of knee replacement surgery (arthroplasty).
  • Table 2A PLOD2 gene burden associations with osteoarthritis and related traits in UK Biobank
  • Table 2B PLOD2 gene burden associations with osteoarthritis and related traits in UK Biobank [00313] Genetic variants in PLOD2 were also evaluated for associations with traits and diseases related to osteoarthritis using summary statistics from approximately 412,000 individuals with genotyping data from the FinnGen cohort.
  • Variants evaluated included chr3:146110290:G:C (rs201501322), a rare (AAF 0.002) stop gain variant (S166Ter) in PLOD2 that is predicted to result in a premature truncation of the PLOD2 protein.
  • This variant may therefore represent a decrease in the abundance and/or activity of the PLOD2 gene product, and this decrease in the abundance and/or activity may result in the observed genetic associations.
  • S166Ter was associated with decreased risk of osteoarthritis, osteoarthritis of the hip, hip replacement surgery (arthroplasty), osteoarthritis of the knee, and knee replacement surgery (arthroplasty).
  • Table 2D PLOD2 variant associations with osteoarthritis and related traits in FinnGen - 168 - Attorney Docket No.54462-772.601
  • Table 2E PLOD2 variant associations with osteoarthritis and related traits in FinnGen [00315]
  • Example 2 Bioinformatic selection of sequences in order to identify therapeutic siRNAs to downmodulate expression of the PLOD2 mRNA
  • Screening sets were defined based on bioinformatic analysis.
  • Therapeutic siRNAs were designed to target human PLOD2. Predicted specificity in human, rhesus monkey, cynomolgus monkey, mouse, rat, rabbit, and dog was determined for sense (S) and antisense (AS) strands. These were assigned a “specificity score” which considers the likelihood of unintended downregulation of any other transcript by full or partial complementarity of an siRNA strand (up to 2 mismatches within positions 2-18) as well as the number and positions of mismatches.
  • S sense
  • AS antisense
  • siRNAs with high specificity and a low number of predicted off-target transcripts provided a benefit of increased targeting specificity.
  • siRNA sequences within the seed region were analyzed for similarity to seed regions of known miRNAs. siRNAs can function in a miRNA like manner via base-pairing with complementary sequences within the 3’-UTR of mRNA molecules. The complementarity typically encompasses the 5‘-bases at positions 2-7 of the miRNA (seed region).
  • siRNA strands containing natural miRNA seed regions can be avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit, and pig are referred to as “conserved”. Combining the “specificity score” with miRNA seed analysis yielded a “specificity category”. This is divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of the siRNA is assigned to a specificity category. [00318] Analysis of the Genome Aggregation Database (gnomAD) to identify siRNAs targeting regions with known SNPs was also carried out to identify siRNAs that may be non-functional in individuals containing the SNP.
  • gnomAD Genome Aggregation Database
  • the siRNAs in subset A had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; and miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off- target frequency: ⁇ 30 human off-target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ⁇ 1% (pos.2-18). [00324] The siRNA sequences in subset A were selected for more stringent specificity to yield subset B.
  • Subset B includes 680 siRNAs whose base sequences are shown in Table 3 subset-B.
  • the siRNAs in subset B had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off- target frequency: ⁇ 20 human off-target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ⁇ 1% (pos.2-18).
  • siRNA sequences in subset B were further selected for absence of seed regions in the AS strand that are identical to a seed region of known human miRNA to yield subset C.
  • Subset C includes 470 siRNAs whose base sequences are shown in Table 3 subset-C.
  • the siRNAs in subset C had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species.
  • AS strand seed region not identical to seed region of known human miRNA
  • Off-target frequency ⁇ 30 human off-target transcripts with 2 or less mismatches by antisense strand
  • SNPs siRNA target sites do not harbor SNPs with a MAF ⁇ 1% (pos.2-18).
  • the siRNA sequences in subset C were also selected for absence of seed regions in the AS or S strands that are identical to a seed region of known human miRNA in addition to having an off-target frequency of ⁇ 30 human off-target transcripts with 2 or less mismatches by antisense strand to yield subset D.
  • Subset D includes 279 siRNAs whose base sequences are shown in Table 3 subset-D.
  • subset D The siRNA sequences in subset D were also selected to have an off-target frequency of ⁇ 20 human off-target transcripts with 2 or less mismatches by antisense strand to yield subset E.
  • Subset E includes 277 siRNAs whose base sequences are shown in Table 3 subset-E.
  • Therapeutic siRNAs were designed to target huma PLOD2 as described above and, in some cases, the PLOD2 sequence of at least one toxicology-relevant species, in this case, the non-human primate (NHP) cynomolgus monkey.
  • siRNAs included in subset F had the following characteristics: - 170 - Attorney Docket No.54462-772.601 [00331] Cross-reactivity: With 19mer in human and cynomolgus monkey PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; and miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off-target frequency: ⁇ 30 human off- target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ⁇ 1% (pos.2-18). Sequences were also prioritized for predicted activity.
  • Subset F includes 310 siRNAs whose base sequences are shown in Table 3 subset-F.
  • the sense strand of any of the siRNAs of subset F comprises siRNA with a particular modification pattern. In this modification pattern, position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification. If position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand.
  • both of these pyrimidines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • position 9 of the sense strand is a purine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. If position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with the 2’F modification in the sense strand.
  • position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. [00335] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand.
  • the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’- fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications.
  • each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof.
  • the oligonucleotide may include pyrimidines.
  • pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.
  • the sense strand comprises purines and pyrimidines.
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- O-methyl and 2’-O-methoxyethyl.
  • all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl.
  • all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O- methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl.
  • all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl.
  • the sense strand may include a 2’ deoxy nucleoside.
  • at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O- methoxyethyl modified nucleoside.
  • at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside.
  • At least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro- modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside.
  • At least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O- methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and - 172 - Attorney Docket No.54462-772.601 all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro.
  • all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. [00342] In some cases, the sense strand of any of the siRNAs of subset F comprises a modification pattern which conforms to these sense strand rules (Table 3 subset-G, Table 4).
  • the antisense strand of any of the siRNAs Table 3 subset-G, Table 4. TABLE 4. Modified Screening Set - 173 - Attorney Docket No.54462-772.601 - 174 - Attorney Docket No.54462-772.601 - 175 - Attorney Docket No.54462-772.601 - 176 - Attorney Docket No.54462-772.601 - 177 - Attorney Docket No.54462-772.601 [00344] Any siRNA among any of subsets A-E may comprise any modification pattern described herein.
  • the modification pattern may still be used with the appropriate number of additional nucleotides added 5’ or 3’ to match the number of nucleotides in the modification pattern. For example, if a sense or antisense strand of the siRNA among any of subsets A-E comprises 19 nucleotides, and a modification pattern comprises 21 nucleotides, UU may be added onto the 5’ end of the sense or antisense strand.
  • siRNA-mediated Knockdown of PLOD2 in SK-MEL-24 Human Stellate Cell Line [00345] siRNAs targeted to the mRNAs of PLOD2 that downregulate levels of these mRNAs leading to a decrease in expression of these proteins when administered to the cultured human fibroblast cell line, SK-MEL-24. [00346] On Day 0, SK-MEL-24 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No.353047) at 0.5 mL per well. [00347] On Day 1, the PLOD2 siRNAs and negative control siRNA master mixes are prepared.
  • Each siRNA master mix contains 350 ⁇ L of Opti-MEM (ThermoFisher Cat. No.31985062) and 3.5 ⁇ L of the respective siRNAs (10 ⁇ M stock).
  • the negative control siRNA master mix contains 350 ⁇ L of Opti-MEM and 3.5 ⁇ L of negative control siRNA (ThermoFisher Cat. No.4390843, 10 ⁇ M stock).
  • 3 ⁇ L of TransIT-X2 (Mirus Cat. No. MIR 6000) is added to each master mix.
  • the Stop Solution (5 ⁇ L/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes.
  • the reverse transcriptase reaction is performed using 20 ⁇ L of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems) for PLOD2 using a BioRad CFX96 Real-Time System (Cat. No.1855195).
  • equivalent quantities (30–50 ⁇ g) of protein are separated by 10% SDS polyacrylamide gels and transferred to polyvinylidene fluoride membranes.
  • Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibodies against PLOD2 at dilutions specified by the manufacturer. After washing three times in TBST, the membranes are incubated - 178 - Attorney Docket No.54462-772.601 with the corresponding horseradish peroxidase-conjugated secondary antibody at a 1:5000 dilution for 1 hour. Bound secondary antibody is detected using an enhanced chemiluminescence system.
  • a decrease in PLOD2 mRNA and protein expression in the SK-MEL-24 cells is expected after transfection with the PLOD2 siRNAs compared to mRNA and protein levels in SK-MEL-24 cells transfected with the non-specific control siRNA 48 hours after transfection.
  • Example 4 ASO-mediated Knockdown of PLOD2 in SK-MEL-24 Human Stellate Cell Line
  • ASOs targeted to the mRNAs of PLOD2 that downregulate levels of these mRNAs, leading to a decrease in expression of these proteins when administered to the cultured human fibroblast cell line, SK-MEL-24.
  • SK-MEL-24 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No.353047) at 0.5 mL per well.
  • the PLOD2 ASOs and negative control ASO master mixes are prepared.
  • Each ASO master mix contains 350 ⁇ L of Opti-MEM (ThermoFisher Cat. No.31985062) and 3.5 ⁇ L of the respective ASOs (10 ⁇ M stock).
  • the negative control ASO master mix contains 350 ⁇ L of Opti-MEM and 3.5 ⁇ L of negative control ASO (ThermoFisher Cat. No.4390843, 10 ⁇ M stock).
  • 3 ⁇ L of TransIT-X2 (Mirus Cat. No. MIR6000) is added to each master mix.
  • the Stop Solution (5 ⁇ L/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes.
  • the reverse transcriptase reaction is performed using 20 ⁇ L of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems) for PLOD2 using a BioRad CFX96 Real-Time System (Cat. No.1855195).
  • equivalent quantities (30–50 ⁇ g) of protein are separated by 10% SDS polyacrylamide gels and transferred to polyvinylidene fluoride membranes.
  • Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibodies against PLOD2 at dilutions specified by the manufacturer. After washing three times in TBST, the membranes are incubated with the corresponding horseradish peroxidase-conjugated secondary antibody at a 1:5000 dilution for 1 hour. Bound secondary antibody is detected using an enhanced chemiluminescence system.
  • a decrease in PLOD2 mRNA and protein expression in the SK-MEL-24 cells is expected after transfection with the PLOD2 ASOs compared to mRNA and protein levels in SK-MEL-24 cells transfected with the non-specific control ASO 48 hours after transfection.
  • Example 5 Determining the activity of GalNAc-conjugated siRNAs targeting human PLOD2 mRNA in mice transfected with AAV8-TBG-h-Gluc-PLOD2 [00357] This experiment evaluates GalNAc-conjugated modified siRNAs targeted to the human PLOD2 mRNA when administered to mice transfected with AAV8 vectors encoding the human PLOD2 gene fused with Gaussia princeps luciferase.
  • AAV8 adeno- associated virus 8
  • AAV8 constructs are prepared, each containing a fusion of the synthetic construct gene for the secreted Gaussia princeps luciferase (NCBI GenBank: LC150601.1) upstream of the open reading frame and parts of the 5’ and 3’ UTRs of the human PLOD2 sequences under the control of the human thyroxine-binding globulin promoter in an AAV2 backbone packaged in an AAV8 capsid.
  • the constructs are designed to encode different fragments of each target transcript under investigation.
  • siRNAs specifically targeting human PLOD2 are subcutaneously injected with 200 ⁇ g of siRNAs specifically targeting human PLOD2, each formulated in 100 ⁇ L PBS.
  • the siRNAs are attached to the GalNAc ligand ETL17.
  • Luciferase activity is quantified using the Gluc GLOW Assay (Nanolight Cat. No.320) according to the manufacturer’s instructions and represents the amount of each target gene fragment transcript produced along with the luciferase transcript. A reduction in luciferase activity indicates a successful reduction in the respective transcript due to siRNA-mediated gene silencing.
  • RNAlater Stabilization Solution (Thermo Fisher, Catalog# AM7020). Serum clinical chemistry analyses are performed (IDEXX Laboratories, Test# 60513) and Gaussia luciferase activity, acting as a proxy for the transcript levels of PLOD2, is measured as described for the Study Day 0 samples.
  • the liver samples are processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using the Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, Cat. No.
  • RNA from the liver lysate is purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations.
  • Preparation of cDNA is performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions.
  • liver PLOD2 mRNA The relative levels of liver PLOD2 mRNA are assessed by RT-qPCR in triplicate on a QuantStudioTM 6 Pro Real-Time PCR System using TaqMan assays designed specifically for human PLOD2 (ThermoFisher), along with the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g1) and PerfeCTa® qPCR FastMix®, - 180 - Attorney Docket No.54462-772.601 Low ROXTM (VWR, Catalog# 101419-222). Data are normalized to the mean mRNA level of PLOD2 in control animals receiving PBS using the delta-delta Ct method.
  • a decrease in human PLOD2 mRNA expression in the liver of mice transfected with AAV8- TBG-h-Gluc-PLOD2 is expected after treatment with the PLOD2 siRNAs, compared to the mRNA levels in control mice treated with PBS.
  • siRNAs specifically targeting human PLOD2 there is an expected decrease in the relative Gaussia princeps luciferase activity corresponding to reduced expression levels of respective PLOD2 transcripts on Study Day 14 compared with Study Day 0.
  • Example 6 Determining the activity of siRNAs targeting PLOD2 mRNA administered via intra- articular injection in mice [00363] This experiment evaluates ETL20-conjugated modified siRNAs targeting PLOD2, aiming to downregulate PLOD2 mRNA levels in the joint and consequently reduce PLOD2 protein abundance when administered to mice via intra-articular injection.
  • mice Six- to eight-week-old female C57BL/6 mice are used in this study, with each group consisting of eight mice. On Day 0, mice are divided into four groups: one group receives intra-articular injection with 10 ⁇ L of sterile PBS as a control, while the other three groups receive intra-articular treatments with modified siRNAs specifically targeting mouse PLOD2. Mice receive their respective treatments via delivery through a syringe of 10 ⁇ L siRNA (100 ⁇ g in PBS) directly into the knee joint. [00365] Prior to dosing, all animals are acclimated and their baseline joint function and mobility are assessed to ensure health and normal joint function. Post-treatment, joint function is monitored to ensure safety and to assess any immediate effects of the siRNA treatment.
  • mice from all groups are euthanized.
  • Joint samples including synovial fluid, tissue and cartilage, are harvested from all animals immediately following euthanasia and placed in RNAlater Stabilization Solution (Thermo Fisher, Catalog# AM7024) to preserve RNA integrity.
  • the joint samples are then processed in homogenization buffer using the Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, Cat. No. P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles.
  • RNA from the joint lysate is purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations.
  • Preparation of cDNA is performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions.
  • the relative levels of joint PLOD2 mRNA are assessed by RT-qPCR in triplicate on a QuantStudioTM 6 Pro Real-Time PCR System using specific TaqMan assays designed for mouse PLOD2, with normalization to the housekeeping gene PPIA (Thermo Fisher, Assay# Mm02342430_g1) to ensure accuracy in quantification and to control for sample input variation.
  • joint tissue samples are analyzed for PLOD2 protein levels through Western blotting, providing a correlation between the decrease in mRNA levels and the resultant impact on protein - 181 - Attorney Docket No.54462-772.601 expression. These analyses confirm the effectiveness of the siRNA in reducing PLOD2 expression in the joint tissue.
  • the expected outcome of this study is a significant reduction in both mRNA and protein levels of PLOD2 in the joints of mice treated with PLOD2 siRNAs compared to those treated with the PBS control.
  • Example 7 Inhibition of PLOD2 in a Rat Model for Osteoarthritis Using Modified siRNAs and ASOs
  • This experiment investigates the role of PLOD2 in osteoarthritis using a rat model where surgical destabilization of the medial meniscus (DMM) simulates joint degradation similar to human osteoarthritis.
  • the experiment will use modified siRNAs and ASOs targeted to the mRNAs of rat PLOD2 individually to modulate their expression and evaluate the effects on joint health and function.
  • the siRNAs and ASOs are attached to the ETL20 ligand for targeted delivery.
  • DMM surgery is performed on 12-week-old female Sprague-Dawley rats to induce an osteoarthritis-like condition.
  • Rats in groups 3-6 receive their respective treatments via intra-articular injection of 50 ⁇ l of siRNA/ASO solution (100 ⁇ g in PBS) on Study Day 28, with subsequent doses administered weekly for a total of six treatments. Rats in groups 1 and 2 receive an equivalent volume of vehicle.
  • Joint health is assessed biweekly using optical coherence tomography (OCT) to visualize cartilage and bone structure, along with pain response measurements (weight-bearing asymmetry and von Frey filament testing) to assess functional outcomes.
  • OCT optical coherence tomography
  • Blood samples are collected at baseline and then biweekly post-treatment.
  • CRP C-reactive protein
  • COMP Cartilage Oligomeric Matrix Protein
  • MMPs Microx Metalloproteinases
  • Joint samples undergo histological analyses to assess cartilage damage, synovitis, and osteophyte formation using standardized scoring systems.
  • Tissues collected for RNA and protein studies are processed using flash frozen and appropriate extraction kits for subsequent qPCR and Western blot analyses, aiming to confirm the expression levels of PLOD2 mRNA and protein and correlate these with observed phenotypic changes.
  • the expected results include a demonstration of the efficacy of PLOD2 siRNA/ASO in modulating the expression of these genes, with concomitant improvements in joint health, as evidenced by OCT, functional assessments, serum biomarkers, and histological analyses of joint tissues. These findings are anticipated to reflect the therapeutic potential of inhibiting PLOD2 in the treatment of osteoarthritis.
  • Total RNA was prepared by homogenizing tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for ten to fifteen cycles of 10 second duration. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Samples with poor RNA yield were excluded from analysis. The levels of PLOD2 mRNA in each joint were assessed by RT-qPCR using TaqMan assays for rat PLOD2 (Cat # Rn00598533_m1) and the rat housekeeping gene PPIA (Cat # Rn00690933_m1) (Table 7).
  • siRNAs injected were normalized to the level in animals receiving vehicle (PBS).
  • the siRNAs injected are depicted in Tables 5 and 6.
  • Table 5 Base siRNA sequences
  • Table 6 Modified siRNA sequences - 183 - Attorney Docket No.54462-772.601 Table 7.
  • Relative mRNA expression Example 9: Screening of siRNAs ETD03672-ETD03676 and ETD03683-ETD03687 targeting human PLOD2 mRNA in mice transfected with AAV8-Gluc-hPLOD2 [00377]
  • the siRNAs are conjugated to the GalNAc ligand ETL17.
  • siRNAs namely ETD03672-ETD03676 and ETD03683-ETD03687.
  • the activities of siRNAs were assessed in mice transiently expressing human PLOD2.
  • the siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand.
  • siRNA sequences that were used are shown in Table 9, where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’-fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage.
  • Nf e.g., Af, Cf, Gf, Tf, or Uf
  • n e.g., a, c, g, t, or u
  • dN e.g., dA, dC, dG, dT, or dU
  • [NUNA] is an
  • mice Six- to eight-week-old female mice (C57Bl/6) were injected with 10 ⁇ L of a recombinant adeno-associated virus 8 (AAV8) vector (5.06 x 10 13 genome copies/mL) and 20 ⁇ L of PBS for a total 30 ⁇ L injection volume by the retroorbital route on Day -15.
  • AAV8 vector adeno-associated virus 8 vector
  • the recombinant AAV8 contains the Gaussia luciferase (GLuc) tag and positions 1-2000 of the open reading frame of the human PLOD2 sequence (ENST00000282903.10) under the control of the human thyroxine binding globulin (TBG) promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-Gluc-hPLOD2_f1_1-2000:oPRE). Circulating levels of the secreted GLuc were measured in plasma by a GLuc GLOW assay (Nanolight Technology, #320-50). Briefly, recombinant Gaussia luciferase protein was diluted in a series to create a standard curve.
  • GLuc Gaussia luciferase
  • GLuc levels in the plasma were measured with GLuc GLOW assay and normalized relative to the PBS control group. Results are shown in Table 10.
  • Table 8 Base siRNA sequences
  • Table 9 Modified siRNA sequences - 185 - Attorney Docket No.54462-772.601 Table 10.
  • Relative GLuc expression Example 10 Screening of human and rat PLOD2 cross-reactive siRNAs ETD03674, ETD03676, ETD03679-ETD03683 in rats [00380] Several siRNAs designed to be cross-reactive with human and rat PLOD2 mRNA were tested for activity in rats. The siRNAs are conjugated to the GalNAc ligand ETL17.
  • siRNAs namely ETD03674, ETD03676, and ETD03679-ETD03683, were assessed in rats.
  • the siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand.
  • siRNA sequences that were used are shown in Table 12, where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’- fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage.
  • Nf e.g., Af, Cf, Gf, Tf, or Uf
  • n e.g., a, c, g, t, or u
  • dN e.g., dA, dC, dG, dT, or dU
  • [NUNA] is an
  • Total RNA was prepared by homogenizing tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for ten to fifteen cycles of 10 second duration. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The levels of PLOD2 mRNA were assessed by RT-qPCR using TaqMan assays for rat PLOD2 (Cat# Rn00598533_m1) and the rat housekeeping gene PPIA (Cat# Rn0690933_m1) (Table 13). Data were normalized to the level in animals receiving vehicle (PBS).
  • PBS rat PLOD2
  • siRNAs injected are depicted in Tables 11 and 12.
  • Table 11 Base siRNA sequences - 186 - Attorney Docket No.54462-772.601
  • Table 12 Modified siRNA sequences Table 13.
  • Relative mRNA expression Example 11 Screening of siRNAs ETD03676-ETD03682 targeting human PLOD2 mRNA in mice transfected with AAV8-Gluc-hPLOD2 [00382] The siRNAs are conjugated to the GalNAc ligand ETL17. The activities of siRNAs, namely ETD03676-ETD03682, were assessed in mice transiently expressing human PLOD2.
  • the siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand.
  • the siRNA sequences that were used are shown in Tables 9, 12, and 15 where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’-fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage.
  • Nf e.g., Af, Cf, Gf, Tf, or Uf
  • n e.g., a, c, g
  • the recombinant AAV8 contains the Gaussia luciferase (GLuc) tag and positions 1800-3749 of the open reading frame of the human PLOD2 sequence (ENST00000282903.10) under the control of the human thyroxine binding globulin (TBG) promoter in an - 187 - Attorney Docket No.54462-772.601 AAV2 backbone packaged in AAV8 capsid (AAV8-Gluc-hPLOD2_f2_1800-3749:oPRE). Circulating levels of the secreted GLuc were measured in plasma by a GLuc GLOW assay (Nanolight Technology, #320-50).
  • recombinant Gaussia luciferase protein was diluted in a series to create a standard curve.
  • mice were bled on Day 12 after subcutaneous injection with whole blood processed to plasma. GLuc levels in the plasma were measured with GLuc GLOW assay and normalized relative to the PBS control group. Results are shown in Table 16.
  • Table 14 Base siRNA sequences
  • Table 15 Modified siRNA sequences Table 16.
  • Relative GLuc expression Example 12 Protective variants in PLOD2 result in altered cellular protein levels of PLOD2 [00385]
  • the cDNA of PLOD2 protein-coding transcript ENST00000282903.10 was cloned into the pcDNA3.1(+) DNA expression vector driven by a constitutive CMV promoter.
  • a representative variant - 188 - Attorney Docket No.54462-772.601 from the osteoarthritis-protective PLOD2 gene burden test (R495Ter, chr3:146079133:G:A) was selected for evaluation, together with the S166Ter (chr3:146110290:G:C) variant.
  • N-terminus FLAG-tagged PLOD2 WT (wild-type), R495Ter and S166Ter constructs were generated.
  • HEK293T human embryonic kidney 293T
  • intracellular PLOD2 was detected as a truncated protein of the predicted molecular weight of ⁇ 19 kDa with reduced levels compared to WT, and extracellular PLOD2 was undetectable by western blot using anti-FLAG antibodies.
  • intracellular PLOD2 showed a truncated protein of the predicted molecular weight of ⁇ 60 kDa with similar levels to WT, and extracellular PLOD2 was undetectable using the anti-FLAG antibody.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets PLOD2. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with PLOD2 variants that include providing an oligonucleotide that targets PLOD2 in a subject.

Description

Attorney Docket No.54462-772.601 TREATMENT OF PLOD2 RELATED DISEASES AND DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/648,147, filed May 15, 2024, all of which applications are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-772_601_SL.xml, created May 5, 2025, which is 15,062,512 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. BACKGROUND [0003] Osteoarthritis is a common degenerative disease that affects one or more joints in the body. Billions of dollars are spent annually for the treatment of arthritis and for lost days of work associated with the disease. The disease is usually oligoarticular but may be generalized. The joints commonly involved include the hips, knees, lower lumbar and cervical vertebrae, proximal and distal interphalangeal joints of the fingers, first carpometacarpal joints, and first tarsometatarsal joints of the feet. Osteoarthritis is a chronic disease characterized by pathologic, degenerative changes in cartilage, bone, synovium, ligament, muscle, periarticular fat and other joint tissues, leading to pain, swelling, and loss of motion. There exists a need for new therapies to treat osteoarthritis and related arthropathies, particularly agents that treat the underlying molecular causes of disease. SUMMARY [0004] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount treats an arthropathy. In some embodiments, the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof. In some embodiments, the treatment of the arthropathy results in, or is intended for, the prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, or a combination thereof. In some embodiments, the effective amount of the oligonucleotide improves: a joint function measurement; a joint structure measurement; a pain measurement; an inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement or synovial biomarker measurement; or an osteoarthritis flare-up measurement. In some embodiments, the joint function measurement comprises range of motion measurement, morning stiffness duration, or grip strength measurement. In some embodiments, the joint function measurement is improved by about 10% or more, as compared to prior to administration. In some - 1 - Attorney Docket No.54462-772.601 embodiments, the joint structure measurement comprises a joint space narrowing, osteophyte formation, subchondral sclerosis measurement, or subchondral cyst measurement. In some embodiments, the joint structure measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the inflammation marker measurement comprises a C-reactive protein measurement (CRP), erythrocyte sedimentation rate (ESR) measurement, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, or IL-6 measurement, or a combination thereof. In some embodiments, the cartilage biomarker measurement comprises a cartilage oligomeric matrix protein (COMP) measurement, aggrecan measurement, type I collagen measurement, type II collagen measurement, proteoglycan measurement, hyaluronic acid measurement, or a combination thereof. In some embodiments, the inflammation marker measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the cartilage biomarker measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the bone biomarkers measurement comprises a type II collagen telopeptide fragments (CTX-II) measurement, type I collagen N-telopeptide (NTX-I) measurement, or a combination thereof. In some embodiments, the bone biomarker measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the synovial biomarkers measurement comprises a MMP (matrix metalloproteinases) measurement, A Disintegrin and Metalloprotease with Thrombospondin motifs (ADAMTS) measurement, a number of pyridinoline cross-links per triple helix collagen measurement, or a combination thereof. In some embodiments, the synovial biomarker measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’,4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2'-O-alkyl, 2’-C-allyl, 2’-O-allyl, 2'-fluoro, or 2'- deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl - 2 - Attorney Docket No.54462-772.601 stearyl, α-tocopherol, stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof. In some embodiments, the lipid comprises a lipid moiety comprising ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. In some embodiments, the lipid moiety comprises ETL20. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N- acetylglucosamine (GlcNAc), or mannose. In some embodiments, the oligonucleotide comprises an integrin or integrin targeting ligand attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the integrin comprises integrin alpha-v-beta-6 or integrin alpha-v-beta-3 (αvβ3) or a combination thereof. In some embodiments, the integrin targeting ligand comprises an arginine-glycine- aspartic acid (RGD) peptide. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the composition is administered by an intra-articular administration. [0005] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises: an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1. In some embodiments, the sense sequence comprises a modification pattern selected from the group consisting of 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. In some embodiments, the antisense sequence comprises a modification pattern selected from the group consisting of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, any one of the following is true with regard to the sense - 3 - Attorney Docket No.54462-772.601 strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’- fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O- methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’- O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O- methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’- - 4 - Attorney Docket No.54462-772.601 fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside. In some embodiments, the composition further comprising a pharmaceutically acceptable carrier. In some embodiments, the composition is administered by an intra-articular administration. [0006] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a sequence of Table 3. [0007] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. [0008] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. [0009] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1; wherein the ASO comprises - 5 - Attorney Docket No.54462-772.601 modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, 155S 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. [0010] Disclosed herein, in some aspects, are methods of treating a subject having an arthropathy, comprising administering an effective amount of the compositions described herein to the subject. In some embodiments, the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof. In some embodiments, the method comprises an intra-articular administration of the effective amount of the composition. In some embodiments, the intra-articular administration is ultrasound guided. [0011] BRIEF DESCRIPTION OF THE DRAWINGS [0012] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: [0013] FIG.1 shows western blots from transfected cells. Whole cell protein lysates were evaluated for intracellular PLOD2 protein (left) and cell culture media supernatants were evaluated for extracellular PLOD2 protein (right). Lysate rows 1-4 (left to right): Empty, WT (wildtype), S166Ter, and R495Ter. Supernatent rows 5-8 (left to right): Empty, WT (wildtype), S166Ter, and R495Ter. Positions for molecular weights 150, 100, 75, 50, 20, and 15 are shown. The top boxes correspond to staining with anti- FLAG antibodies while the bottom (left) box corresponds to the GAPDH control. DETAILED DESCRIPTION [0014] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of - 6 - Attorney Docket No.54462-772.601 disease and provide applicable treatments. A GWAS can utilize genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.” [0015] Functional annotation of variants and/or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease-causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target. [0016] Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend on several factors including the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue and a relevant indication. [0017] PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) is located on human chromosome 3 (3q24), and also contains 19 exons. PLOD2 may include 737 amino acids and have a mass of about 84686 Da. PLOD2 is an enzyme that post-translationally modifies collagen by hydroxylating lysine residues in collagen molecules. This modification is crucial for the stability and cross-linking of collagen fibers within the extracellular matrix (ECM). The hydroxylation of lysine residues enables further glycosylation by COLGALT2 (collagen beta(1-O)galactosyltransferase 2). PLOD2 may be intracellular. PLOD2 may be extracellular. PLOD2 may be expressed in chondrocytes. PLOD2 may be expressed in osteoblasts. PLOD2 may be expressed in fibroblasts. PLOD2 may be expressed in synoviocytes. PLOD2 may be expressed in articular joint. PLOD2 may be expressed in articular cartilage. PLOD2 may be expressed in synovium. PLOD2 may be expressed in synovial membrane. An example of a PLOD2 protein amino acid sequence, and further description of PLOD2 protein is included at uniprot.org under accession no. ENST00000282903.10. - 7 - Attorney Docket No.54462-772.601 [0018] Here, it is shown that genetic variants that may result in loss of function of the PLOD2 gene in humans are associated with decreased risk of osteoarthritis. PLOD2 inhibition may lead to an increase in aggrecan levels and may offer a promising approach for the treatment of osteoarthritis by promoting cartilage integrity and potentially slowing down the degenerative process in affected joints. PLOD2 inhibition may lead to changes in the post-translational modifications of collagen and may offer a promising approach for the treatment of osteoarthritis by promoting resolution of stiffness and pain in affected joints. Therefore, inhibition of PLOD2 may serve as a therapeutic strategy for treatment of various kinds of osteoarthritis, e.g., osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet; temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee. [0019] Disclosed herein, are methods or compositions are oligonucleotides that inhibit or target PLOD2. Where inhibition or targeting of PLOD2 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting PLOD2 RNA or PLOD2 protein. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the PLOD2 gene using an oligonucleotide described herein, PLOD2 protein may be inhibited or targeted as a result of there being less production of PLOD2 protein by translation of the PLOD2 RNA; or PLOD2 protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a PLOD2 RNA and reduces production of PLOD2 protein from the PLOD2 RNA. Thus, targeting PLOD2 may refer to binding a PLOD2 RNA and reducing PLOD2 RNA levels or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating an osteoarthritis by providing an oligonucleotide that targets PLOD2 to a subject in need thereof. In certain aspects, disclosed herein is a method of treating a subject having an osteoarthritis, comprising administering an effective amount of the siRNAs disclosed herein to the subject. [0020] In some embodiments, the siRNAs described herein comprise a sense strand and an antisense strand. In some embodiments, the sense strand comprises any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 or the antisense strand comprises any one of SEQ ID NOs: 3733- 7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189. [0021] In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 1S to 155S or 1AS to 69AS. In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 54S, 58S, 7AS, 51AS, or 46AS. In some embodiments, the sense strand comprises modification pattern 54S. In some embodiments, the sense strand comprises modification pattern 58S. In some embodiments, the antisense strand comprises modification pattern 7AS. In some embodiments, the antisense strand comprises modification pattern 46AS. In some embodiments, the antisense strand comprises modification pattern 51AS. - 8 - Attorney Docket No.54462-772.601 I. COMPOSITIONS [0022] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets PLOD2. In some embodiments, the composition consists of an oligonucleotide that targets PLOD2. In some embodiments, the oligonucleotide reduces PLOD2 mRNA expression in the subject. In some embodiments, the oligonucleotide reduces PLOD2 protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein. [0023] Some embodiments include a composition comprising an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases PLOD2 mRNA or PLOD2 protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases PLOD2 mRNA levels in a cell or tissue. In some embodiments, the cell is a chondrocyte, an osteoblast, a synoviocyte, or a fibroblast. In some embodiments, the tissue is articular joint tissue. In some embodiments, the tissue is articular cartilage. In some embodiments, the tissue is synovium. In some embodiments, the tissue is synovial membrane. In some embodiments, the fluid is synovial fluid. In some embodiments, the PLOD2 mRNA levels are each decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by about 10% or more, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the PLOD2 mRNA levels are each decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0024] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases PLOD2 protein levels in a cell, fluid or tissue. In some embodiments, the cell is a chondrocyte, an osteoblast, a synoviocyte or a fibroblast. In some embodiments, the tissue is articular joint tissue. In some embodiments, the tissue is articular - 9 - Attorney Docket No.54462-772.601 cartilage. In some embodiments, the tissue is synovium. In some embodiments, the tissue is synovial membrane. In some embodiments, the fluid is a blood, serum, synovial or plasma sample. In some embodiments, the PLOD2 protein levels are each decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by about 10% or more, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the PLOD2 protein levels are each decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0025] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount diminishes an adverse phenotype of arthropathy in the subject. The arthropathy may include osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, or degenerative joint disease. In some embodiments, the diminishing the adverse phenotype of arthropathy results in, or is intended for, the prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, or a combination thereof. In some embodiments, the adverse phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. - 10 - Attorney Docket No.54462-772.601 [0026] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount enhances a protective phenotype of an arthropathy. The arthropathy may include osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, or degenerative joint disease. In some embodiments, the enhancement a protective phenotype of an arthropathy results in, or is intended for, the prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, or a combination thereof. In some embodiments, the protective phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 10% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. [0027] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a joint function measurement. The joint function measurement may include a measurement of range of motion, morning stiffness duration, or grip strength. In some embodiments, the joint function measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. - 11 - Attorney Docket No.54462-772.601 In some embodiments, the joint function measurement is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the joint function measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. [0028] A joint structure may be affected by an arthropathy. For example, some inflammatory arthropathies that may include osteoarthritis, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, or degenerative joint disease that may lead to joint space narrowing, osteophyte formation, subchondral sclerosis, or subchondral cysts that may be treated using a composition comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount change or improves a joint structure measurement of the subject. In some embodiments, the joint structure measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the joint structure measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or by a range defined by any of the two aforementioned percentages. - 12 - Attorney Docket No.54462-772.601 [0029] In some embodiments, the joint structure measurement includes a joint space measurement e.g., joint space narrowing measurement. As cartilage deteriorates or wears away, narrowing of the joint space of the affected joint can be observed (joint space narrowing). Given the difficulty in measuring cartilage, joint space width (JSW) measurements are often considered a surrogate for articular cartilage thickness as such measurements involve determining the distance between two bones (e.g., using X-ray techniques). Without being bound by any theory, an increase in the JSW is an indicator of cartilage growth. Methods of measurement of JSW can be completed following radiographic imaging of the affected joint. Measurements can be either manual using calipers or a simple graduated ruler and a micrometric eyepiece or semiautomated using computer software. In some embodiments, JSW measurements can involve radiographic images (e.g., X-ray) taken of the knee. For example, one or more of metatarsophalangeal, fixed flexion, semiflexed anteroposterior (AP) and Lyon-Schuss radiographs can be used to obtain the measurement. In some embodiments, the subject is imaged while standing. For example, standing, fixed-flexion (Synaflexer), posterior-anterior (PA) radiographs. In some embodiments, the joint structure measurement includes osteophyte formation. In some embodiments, the joint structure measurement includes subchondral sclerosis measurement. In some embodiments, the joint structure measurement includes subchondral cysts measurement. The measurement includes measuring the volume, area, depth of osteophytes, subchondral cysts, or subchondral sclerosis. [0030] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves osteophyte formation in the subject. In some embodiments, the osteophyte formation is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by about 10% or more, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the osteophyte formation is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0031] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves subchondral sclerosis in the subject. In some embodiments, the subchondral sclerosis is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by about 10% or more, as compared to prior to administration. In some - 13 - Attorney Docket No.54462-772.601 embodiments, the subchondral sclerosis is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the subchondral sclerosis is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0032] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves subchondral cysts in the subject. In some embodiments, the subchondral cysts are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by about 10% or more, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the subchondral cysts are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0033] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount decreases pain (as assessed by visual analogue scale (VAS), WOMAC pain subscale) in the subject. In some embodiments, the pain is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the pain is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the pain is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the pain is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the pain is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the pain is decreased by no more than about 20%, no more - 14 - Attorney Docket No.54462-772.601 than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the pain is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0034] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves (e.g., decreases) the levels of inflammation markers in the subject. Representative examples of inflammation markers include, but are not limited to, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6. In some embodiments, the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by about 10% or more, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels of inflammation markers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0035] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves the levels of cartilage biomarkers in the subject. Representative examples of cartilage biomarker include, but are not limited to, Cartilage Oligomeric Matrix Protein (COMP), aggrecan, type I collagen, type II collagen, proteoglycans or hyaluronic acid. In some embodiments, the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by about 10% or more, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by no more than about 20%, no more - 15 - Attorney Docket No.54462-772.601 than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels of cartilage biomarkers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0036] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves the levels of synovial biomarkers in the subject. Representative examples of synovial biomarkers include, but are not limited to, matrix metalloproteinases (MMPs), disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS), and the number of pyridinoline cross-links per triple helix collagen. Cartilage destruction in osteoarthritis (OA) is thought to be mediated by two main enzyme families; the matrix metalloproteinases (MMPs) are responsible for cartilage collagen breakdown, whereas enzymes from the 'a disintegrin and metalloproteinase domain with thrombospondin motifs' (ADAMTS) family mediate cartilage aggrecan loss. In some embodiments, the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by about 10% or more, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels of synovial biomarkers are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0037] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a patient-reported outcome measurement (PROMs) including, but not limited to, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Medical Outcome Studies Short Form 36 (SF-36), Knee Disability and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), Disabilities of the Arm, Shoulder and Hand (DASH), EUROQoL (EQ5-D), Medical Outcomes Study Short Form 12-item (SF12), Hip Disability and Osteoarthritis Outcome Score (HOOS), Pain Catastrophizing (PCS) and Oxford Hip Score (OHS) in the subject. In some embodiments, the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or - 16 - Attorney Docket No.54462-772.601 more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0038] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a physical function measurement in the subject, including, but not limited to, 6-minute walk test, timed up-and-go test. In some embodiments, the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0039] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves a quality-of-life assessment or measurement in the subject, including, but not limited to, Medical Outcome Studies Short Form 36 (SF- 36), EUROQoL (EQ-5D). In some embodiments, the measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the measurement is improved by no - 17 - Attorney Docket No.54462-772.601 more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0040] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves (e.g., decreases) osteoarthritis flare-ups (i.e. exacerbations) in the subject. In some embodiments, the flare-ups are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the flare-ups are improved by about 10% or more, as compared to prior to administration. In some embodiments, the flare-ups are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the flare-ups are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the flare-ups are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the flare-ups are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the flare-ups are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0041] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount improves radiographic progression (assessed by Kellgren-Lawrence grading scale) in the subject. In some embodiments, the progression is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the progression is improved by about 10% or more, as compared to prior to administration. In some embodiments, the progression is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the progression is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the progression is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the progression is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the progression is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. - 18 - Attorney Docket No.54462-772.601 A. siRNAs [0042] In some embodiments, the composition comprises an oligonucleotide that targets PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. [0043] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length. [0044] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length huma PLOD2 mRNA sequence such as SEQ ID NO: 1. In some embodiments, at least one of the sense strands and the antisense strands comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 1. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 1. Any of the aforementioned siRNAs may include a sense strand of SEQ ID NO: 1, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of SEQ ID NO: 1, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand of the composition 5’ 7 -3’ and an antisense strand of composition 5 7 -3’. Where (N) 0-7 are independently nucleic acid stretches of 0 to 7 nucleotides, ( ) contain at least 15 contiguous nucleotides from Tables 3-5 and contain no cyclic ribose nucleotides with 2’ hydroxyl groups. The sense and antisense strand have 1-5 phosphorothioate inter-nucleotide linkages and either the sense or antisense strand has a targeting ligand attached to the 5’ or 3’ end. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand composition. The targeting ligand may be a lipid - 19 - Attorney Docket No.54462-772.601 moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal- 6]s[Gal-6]s[Gal-6], Janssen, Arbutus THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety are ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. [0045] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair. [0046] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. [0047] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. [0048] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a huma PLOD2 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a huma PLOD2 mRNA. [0049] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate PLOD2, mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a - 20 - Attorney Docket No.54462-772.601 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate PLOD2 mRNA. [0050] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a huma PLOD2 mRNA and less than or equal to 20 human off-target transcripts, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 10 human off-target transcripts, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 30 human off-target transcripts, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 40 human off-target transcripts, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 50 human off-target transcripts, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 10 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 20 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 30 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 40 human off-target transcripts, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a huma PLOD2 mRNA and less than or equal to 50 human off-target transcripts, with no more than 3 mismatches in the antisense strand. [0051] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a huma PLOD2 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos.2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182- 8185 in PLOD2. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, at least 80% identical to any one of SEQ ID NOs: 2-3732 in PLOD2, at least 85% identical to of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, at least 90% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or at least 95% identical to any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2. The sense strand sequence - 21 - Attorney Docket No.54462-772.601 may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. [0052] In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2-3732, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin-targeting ligand. The sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, or LDL receptor ligand. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand. [0053] Any of the aforementioned siRNAs may include a strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 5 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732 in PLOD2 is modified to - 22 - Attorney Docket No.54462-772.601 an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2- 3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112- 8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2- 3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 2-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185 in PLOD2 is modified to an C. [0054] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, at least 80% identical to any one of SEQ ID NOs: 3733-7463 in PLOD2, at least 85% identical to of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, at least 90% identical to any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, or at least 95% identical to any one of SEQ ID NOs: 3733-7463 in PLOD2. In - 23 - Attorney Docket No.54462-772.601 some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3733-7463 in PLOD2, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, or LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167- 8173, or 8186-8189 in PLOD2. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand. [0055] Any of the aforementioned siRNAs may include a strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a strand sequence wherein the 3’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: - 24 - Attorney Docket No.54462-772.601 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an A. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093- 8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 in PLOD2 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186- 8189 in PLOD2 is modified to an C. [0056] In some embodiments, any of the aforementioned siRNA comprising a sense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein - 25 - Attorney Docket No.54462-772.601 receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NOs: 1-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 1-3732, 8084-8092, 8112-8125, 8160-8166, or 8182-8185, thymine (T) may be replaced with uracil (U). In some embodiments, any of the aforementioned siRNA comprising an antisense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189. The antisense stand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep- 2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety comprises including, but not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 3733-7463, 8093-8101, 8126-8139, 8167-8173, or 8186-8189 thymine (T) may be replaced with uracil (U). [0057] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense - 26 - Attorney Docket No.54462-772.601 strand or antisense strand sequence of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand of subset A, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset A, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0058] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand of subset B, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset B, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. - 27 - Attorney Docket No.54462-772.601 [0059] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand of subset C, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset C, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0060] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any of the aforementioned siRNAs may include a sense strand of subset D, wherein the nucleotide at the 3’ end of - 28 - Attorney Docket No.54462-772.601 the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset D, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0061] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand of subset E, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset E, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0062] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset F. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset F. Any of the aforementioned siRNAs may include a sense strand of - 29 - Attorney Docket No.54462-772.601 subset F, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset F, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0063] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset G. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand of subset G, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset G, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. [0064] In some embodiments, any of the aforementioned siRNA comprising a sense strand or antisense stand comprises a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense or anti sense strand sequence of one of subset A, subset B, subset C, subset D, subset E, or subset F. The sense strand or antisense stand may comprise a lipid moiety. The sense or antisense strand may comprise a GalNAc moiety. The sense strand or antisense stand may comprise an integrin or an integrin targeting ligand. The sense strand or antisense stand may comprise an angiopep-2. The sense strand or antisense stand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The sense strand or antisense stand may comprise an LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 1-29070, thymine (T) may be replaced with uracil (U). - 30 - Attorney Docket No.54462-772.601 [0065] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3 and 4. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Tables 3 and 4 is modified by substitution of the 5’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0066] The siRNA may comprise the sense strand and/or the antisense strand base sequence (e.g., unmodified sequence, or base sequence with other modifications) of an siRNA in any table included herein; or may include a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; or may include a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some cases, the sequence does not include an overhang (e.g., UU) that is included in a table. [0067] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A (Table 3-SubsetA), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. - 31 - Attorney Docket No.54462-772.601 [0068] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B (Table 3-SubsetB), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0069] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C (Table 3-Subset C), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0070] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D (Table 3-Subset D), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned - 32 - Attorney Docket No.54462-772.601 siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0071] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E (Table 3-Subset E), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0072] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F (Table 3-Subset F), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. B. ASOs [0073] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length. - 33 - Attorney Docket No.54462-772.601 [0074] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human PLOD mRNA sequence such as SEQ ID NO: 1; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 1. C. Modified oligonucleotides [0075] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include improved toxicity or improved pharmacokinetics. [0076] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends. [0077] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or - 34 - Attorney Docket No.54462-772.601 more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages. [0078] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), 2’,4’ constrained ethyl nucleic acid, hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2’-C-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O- alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics. [0079] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure: - 35 - Attorney Docket No.54462-772.601 wherein the base can be any pyrimidine or purine. [0080] An unlocked nucleic acid may comprise the following structure: wherein the base can be any pyrimidine or purine. [0081] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site: are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond. [0082] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below: methylphosphonate 2’-O-methyl Uridine). - 36 - Attorney Docket No.54462-772.601 [0083] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides. [0084] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Examples of moieties include an integrin targeting ligand, a hydrophobic moiety, a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO. [0085] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. [0086] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. - 37 - Attorney Docket No.54462-772.601 [0087] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof. [0088] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’-deoxy nucleoside. [0089] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. [0090] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- - 38 - Attorney Docket No.54462-772.601 methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. [0091] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; an overhang region at the 3 end of the sense strand having at least 3 contiguous phosphorothioated nucleotides; and an overhang region at the 3' end of the antisense strand having at least 3 contiguous phosphorothioated nucleotides. [0092] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; and an overhang region at the 3’ end of the sense strand having at least 3 contiguous phosphorothioated nucleotides. [0093] In some embodiments, the oligonucleotide includes two to eight oligonucleotides attached through a linker. The linker may be hydrophobic. In some embodiments, the oligonucleotides independently have substantial chemical stabilization (e.g., at least 40% of the constituent bases are chemically-modified). In some embodiments, the oligonucleotides have full chemical stabilization (i.e., all of the constituent bases are chemically-modified). In some embodiments, the oligonucleotide includes one or more single-stranded phosphorothioated tails, each independently having two to twenty nucleotides. In some embodiments, each single-stranded tail has eight to ten nucleotides. [0094] In certain embodiments, a compound (e.g., moiety attached to the oligonucleotide) includes three properties: (1) a branched structure, (2) full metabolic stabilization, and (3) the presence of a single- stranded tail comprising phosphorothioate linkers. In a particular embodiment, a compound has 2 or 3 branches. The increased overall size of the branched structures promote increased uptake. Also, without being bound by a particular theory of activity, multiple adjacent branches (e.g., 2 or 3) allow each branch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release. The compound may include an oligonucleotide described herein, as part of the compound. [0095] In certain embodiments, a compound includes the following properties: (1) two or more branched oligonucleotides linked via a non-natural linker (2) substantially chemically stabilized, e.g., wherein more than 40%, optimally 100%, of oligonucleotides are chemically modified (e.g., no RNA and optionally no DNA); and (3) phosphorothioated single oligonucleotides containing at least 3, optimally 5- 20 phosphorothioated bonds. [0096] In some embodiments, the oligonucleotide comprises a phosphate at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate at a 3’ end. In some embodiments, the - 39 - Attorney Docket No.54462-772.601 oligonucleotide comprises a phosphate mimic at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 3' end. [0097] The oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof. [0098] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa. [0099] In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. [00100] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines. [00101] In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl - 40 - Attorney Docket No.54462-772.601 modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’-fluoro modified purines. [00102] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules. [00103] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between - 41 - Attorney Docket No.54462-772.601 positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules. [00104] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules. [00105] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group includes a cell receptor ligand, such as an integrin targeting ligand. Integrins may include a family of transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. In some embodiments, the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 (αvβ6) bay be an example of an epithelial-specific integrin αvβ6 may be a receptor for an ECM protein or TGF-beta latency-associated peptide (LAP). Integrin αvβ6 may be expressed in a cell or tissue. Integrin αvβ6 may be expressed or upregulated in injured pulmonary epithelium. [00106] In some embodiments, the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin αvβ6. An integrin targeting ligand may include a compound that has affinity for integrin αvβ6 or integrin alpha-v-beta-3 (αvβ3), may be useful as a ligand to facilitate targeting or delivery of the oligonucleotide to which it is attached to a particular cell type or tissue (e.g., to cells expressing integrin αvβ3 or αvβ6). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the oligonucleotide-integrin targeting ligand conjugates are selectively internalized by chondrocytes, either through receptor-mediated endocytosis or by other means. [00107] Examples of targeting groups useful for delivering the oligonucleotide that include integrin targeting ligands may be based upon peptides or peptide mimics containing an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide, and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. The RGD peptide may be linear. The RGD peptide may be cyclic. An RGD peptide may include a D-amino acid. In some embodiments, - 42 - Attorney Docket No.54462-772.601 the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises Cyclo(- Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides. For example, the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide. [00108] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. [00109] In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-methyl modified pyrimidines. [00110] In some cases, position 9 of a strand of the oligonucleotide can be a 2’-deoxy. In these cases, 2’-F and 2’-OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules. [00111] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- - 43 - Attorney Docket No.54462-772.601 numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. [00112] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’- fluoro-modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro-modified pyrimidines in a row. [00113] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. [00114] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered - 44 - Attorney Docket No.54462-772.601 positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. [00115] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’-end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans-vinylphosphonate or cis-vinylphosphonate. The 5’-end group may include an extra 5’ phosphate. A combination of 5’-end groups may be used. [00116] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used. [00117] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below. 5’ vinylphosphonate 2’ O Methyl Uridine - 45 - Attorney Docket No.54462-772.601 [00118] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery. [00119] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. 1. Hydrophobic moieties [00120] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof. [00121] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof. [00122] In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis- Othexadecyl glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoy)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or a combination thereof. The lipophilic moiety may include a steroid such as cholesterol. The lipophilic moiety may include retinoic acid. The lipophilic moiety may include cholic acid. The lipophilic moiety may include adamantane acetic acid. The lipophilic moiety may include 1-pyrene butyric acid. The lipophilic moiety may include dihydrotestosterone. The lipophilic moiety may include 1,3-bis-O(hexadecyl) glycerol. The lipophilic moiety may include geranyloxyhexyanol. The lipophilic moiety may include hexadecylglycerol. The lipophilic moiety may - 46 - Attorney Docket No.54462-772.601 include borneol. The lipophilic moiety may include menthol. The lipophilic moiety may include 1,3- propanediol. The lipophilic moiety may include a heptadecyl group. The lipophilic moiety may include palmitic acid. The lipophilic moiety may include myristic acid. The lipophilic moiety may include O3- (oleoy]lithocholic acid. The lipophilic moiety may include O3-(oleoyl)cholenic acid. The lipophilic moiety may include ibuprofen. The lipophilic moiety may include naproxen. The lipophilic moiety may include dimethoxytrityl. The lipophilic moiety may include phenoxazine. [00123] In some embodiments, the lipophilic moiety comprises a hydrocarbon chain. The hydrocarbon chain may comprise or consist of a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid. [00124] In some embodiments, the oligonucleotide includes one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand of the oligonucleotide, optionally via a linker or carrier. For instance, some embodiments provide an oligonucleotide comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via a linker or carrier. In some embodiments, the lipophilicity of the lipophilic moiety, measured by octanol-water partition coefficient, logP, exceeds 0. [00125] In some embodiments, the lipophilic moiety is an aliphatic, cyclic such as alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol), a linear or branched aliphatic hydrocarbon, or an aromatic. Exemplary lipophilic moieties may include lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O-(hexadecyl) glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. Suitable lipophilic moieties may also include those containing a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl), and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. The functional group may be useful to attach the lipophilic moiety to the oligonucleotide. In some embodiments, the lipophilic moiety contains a saturated or unsaturated C6- C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds. [00126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some - 47 - Attorney Docket No.54462-772.601 embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide. [00127] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and/or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid. [00128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified. [00129] In some embodiments, the oligonucleotide comprises any aspect of the following structure: . In some embodiments, the oligonucleotide comprises any aspect of the following structure: . some embodiments, the oligonucleotide comprises any aspect of the following structure: - 48 - Attorney Docket No.54462-772.601 . In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the oligonucleotide does not comprise a phenyloctyl group. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R is not an octane (C8). In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the lipid moiety has at least one degree of unsaturation. In some embodiments, the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid. [00130] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue. [00131] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety - 49 - Attorney Docket No.54462-772.601 includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons. Table 1: Hydrophobic moiety examples - 50 - Attorney Docket No.54462-772.601 - 51 - Attorney Docket No.54462-772.601 - 52 - Attorney Docket No.54462-772.601 [00132] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide. [00133] The lipid moiety may comprise or consist of the following structure: . In some embodiments, the lipid moiety comprises or consists of the following structure: . some embodiments, the lipid moiety comprises the following some embodiments, the lipid moiety comprises or consist of the following structure: . some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some - 53 - Attorney Docket No.54462-772.601 embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. In some embodiments, R is not octane. In some embodiments, R is a carbon containing 4-7 or 9-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group. [00134] In some embodiments, the 5’ hydrophobic moiety comprises any one of the following line indicates a covalent connection to the end of the 5’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane. In some embodiments, the alkyl group contains 4–7 or 9–18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5’ hydrophobic moiety comprises a hydrophobic moiety in Table 1. In some embodiments, the 5’ hydrophobic moiety comprises phenyl para C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 0–3. In some embodiments, n is 1–3. In some embodiments, n is 1. In some embodiments n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof. In some embodiments, the 5’ hydrophobic moiety is not a phenyloctyl group. [00135] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl - 54 - Attorney Docket No.54462-772.601 linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide. [00136] In some embodiments, when the lipid moiety comprises the structure: , Ris not an octyl group. In some embodiments, R is an unsaturated hydrocarbon. In some embodiments, R is a monounsaturated acyl group. In some embodiments, the monounsaturated acyl group is unsaturated at the omega-3, omega-5, omega-6, omega-7, omega-8, or omega-9 position. In some embodiments, the unsaturated hydrocarbon is a polyunsaturated fatty acyl group. In some embodiments, the polyunsaturated fatty acyl group is unsaturated at least at the omega-3, omega-5, omega-6, omega-7, omega-, omega-9 position, or a combination thereof. [00137] The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. [00138] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties. [00139] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a - 55 - Attorney Docket No.54462-772.601 phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows: . n some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands. - 56 - Attorney Docket No.54462-772.601 [00140] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol). [00141] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue. 2. Sugar moieties [00142] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte. [00143] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2, or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. [00144] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide. [00145] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc - 57 - Attorney Docket No.54462-772.601 moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II): or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2; Q is selected from: C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1 is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, - N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, - OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2 is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7 , -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; R3 and R4 are each independently selected from: -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7 , -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; - 58 - Attorney Docket No.54462-772.601 each R5 is independently selected from: -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7 , -N(R7)C(O)N(R7)2, - N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6 is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7 , - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7 is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, - O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl. [00146] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1 is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2- - 59 - Attorney Docket No.54462-772.601 NR7. In some embodiments, R1 is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O- )S-, and -OP(OR7)O-. In some embodiments, R1 is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and -OP(OR7)O-. In some embodiments, R1 is selected from - OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7 and - OC(O)R7. In some embodiments, R3 is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R3 is selected from -OR7 -SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3 is selected from -OR7 - and -OC(O)R7. In some embodiments, R4 is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R4 is selected from -OR7 -SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R4 is selected from -OR7 - and -OC(O)R7. In some embodiments, R5 is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5 is selected from -OC(O)R7 and -N(R7)C(O)R7. In some embodiments, each R7 is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O- C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, - NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, and -NH(C1-6 alkyl). In some embodiments, each R7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl; R1 is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and - OP(OR7)O-; R2 is C1 alkyl substituted with -OH or -OC(O)CH3; R3 is -OH or -OC(O)C some embodiments, the compound comprises: , - 60 - Attorney Docket No.54462-772.601 - 61 - Attorney Docket No.54462-772.601 - 62 - Attorney Docket No.54462-772.601 - 63 - Attorney Docket No.54462-772.601 - 64 - Attorney Docket No.54462-772.601 . [00147] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte. [00148] Some embodiments include the following, where J is the oligonucleotide: - 65 - Attorney Docket No.54462-772.601 include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. [00149] Some embodiments include the following, where J is the oligonucleotide: . J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. [00150] Some embodiments include the following, where J is the oligonucleotide: - 66 - Attorney Docket No.54462-772.601 include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00151] Some embodiments include the following, where J is the oligonucleotide: . The structure in this compound attached to the oligonucleotide (J) is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. - 67 - Attorney Docket No.54462-772.601 J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00152] Some embodiments include the following, where J is the oligonucleotide: one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. [00153] Some embodiments include the following, where J is the oligonucleotide: - 68 - Attorney Docket No.54462-772.601 . J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. [00154] Some embodiments include the following, where J is the oligonucleotide: . may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00155] Some embodiments include the following, where J is the oligonucleotide: - 69 - Attorney Docket No.54462-772.601 . The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00156] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide: - 70 - Attorney Docket No.54462-772.601 [00157] Some embodiments include the following, where the phosphate or “5’” indicates a connection [00158] Some embodiments include the following, where J is the oligonucleotide: include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00159] Some embodiments include the following, where J is the oligonucleotide: - 71 - Attorney Docket No.54462-772.601 . The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide. [00160] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), Formula III, - 72 - Attorney Docket No.54462-772.601 Formula V, or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; - 73 - Attorney Docket No.54462-772.601 x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20; Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7 , -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1 is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, - OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R7 is independently selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl. [00161] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: - 74 - Attorney Docket No.54462-772.601 [00162] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00163] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: . [00164] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00165] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: - 75 - Attorney Docket No.54462-772.601 . [00166] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00167] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides: - 76 - Attorney Docket No.54462-772.601 [00168] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances 2-4 GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide. - 77 - Attorney Docket No.54462-772.601 [00169] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide: - 78 - Attorney Docket No.54462-772.601 - 79 - Attorney Docket No.54462-772.601 or - 80 - Attorney Docket No.54462-772.601 . [00170] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide. [00171] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: . The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. - 81 - Attorney Docket No.54462-772.601 [00172] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O: . The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: . The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more - 82 - Attorney Docket No.54462-772.601 phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. [00174] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide: [00175] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide. [00176] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide: - 83 - Attorney Docket No.54462-772.601 . [00177] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. 3. siRNA modification patterns [00178] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5’- NfsnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3. In some embodiments, the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN- moiety-3’. In some embodiments, the sense strand comprises modification pattern 5S: 5’- nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3’. In some embodiments, the moiety in modification pattern 4S or 5S is a lipophilic moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’- NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3’. In some - 84 - Attorney Docket No.54462-772.601 embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 10S: 5’- NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 11S: 5’-nsnsNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’-NfsnsNfnNfnNfnNfnNfnnnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 13S: 5’- nsnsnnnnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 14S: 5’-snnnnnnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15S: 5’-snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 16S: 5’- snnnnNfnNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 17S: 5’-snnnnnNfNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 18S: 5’-snnnnnnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 19S: 5’-snnnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 21S: 5’-snnnnNfNfnnNfNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 22S: 5’- snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 23S: 5’-snnnnnNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 24S: 5’-snnnnnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25S: 5’-snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNfNfNfNfnnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 27S: 5’- snnnnnnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 28S: 5’-snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’-snnnnnnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 30S: 5’-snnnnNfNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 31S: 5’-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 32S: 5’- snnnnnnNfNfdNNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 33S: 5’-snnnnNfnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34S: 5’-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S: 5’-snnnnnnNfNfNfNfnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36S: 5’- snnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S: 5’-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S: 5’-snnnnNfnNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39S: 5’-snnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40S: 5’- - 85 - Attorney Docket No.54462-772.601 snnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 41S: 5’-snnnnnnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 42S: 5’-snnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 43S: 5’-snnnnnnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S: 5’-snnnnNfnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 45S: 5’-snnnnnNfnnNfNfnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 46S: 5’- snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S: 5’-snnnnnNfNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 48S: 5’-nnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 49S: 5’-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 50S: 5’- nnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 51S: 5’-nnnnNfNfNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 52S: 5’-snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 53S: 5’-snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 54S: 5’- snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S: 5’-snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 56S: 5’-snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 57S: 5’-snnnnnmNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S: 5’- nnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S: 5’-snsnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 60S: 5’-snnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61S: 5’-snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62S: 5’- snnnnmnNfNfNfNfnnnnmnnnninsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63S: 5’-snnnnmnNfNfNfNfnnnnmnninnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64S: 5’-nnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S: 5’-nsnsnnmnN(C16)NfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66S: 5'- nnnnnnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67S: 5'-nnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'-nnnnnnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'-nnnnnNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 70S: 5'-nnnnnNfnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 71S: 5'-nnnnnNfnNfNfnNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 72S: 5'- - 86 - Attorney Docket No.54462-772.601 nnnnnnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 73S: 5'-nnnnNfnNfnNfnnnnnnnnnnsnsn-3. In some embodiments, the sense strand comprises modification pattern 74S: 5'-nnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'-nnnnNfnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'-nnnnNfNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 78S: 5'- nnnnnNfNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 79S: 5'-nnnnnNfNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 80S: 5'-nnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 81S: 5'-nnnnNfnnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 82S: 5'-nnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 83S: 5'-nnnnNfnNfnNfnNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 84S: 5'- nnnnNfNfnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 85S: 5'-nnnnNfNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 86S: 5'-nnnnnnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 87S: 5'-nnnnnnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'-nnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 89S: 5'-nnnnnNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'- nnnnnNfnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 91S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 92S: 5'-nnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 93S: 5'-nnnnNfnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 94S: 5'-nnnnNfnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 95S: 5'-nnnnNfnNfNfNfNfnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 96S: 5'- nnnnNfNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 97S: 5'-nnnnnnnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 98S: 5'-nnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 99S: 5'-nnnnnnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 100S: 5'-nnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 101S: 5'- nnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'-snnnnnNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 104S: 5'-snnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: 5'- - 87 - Attorney Docket No.54462-772.601 snnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 106S: 5'-snnnnNfnnNfNfnnnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’-snNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 109S: 5’- snnnnnmNfNfNfNfnnnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNfNfnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 111S: 5’-NfsnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 112S: 5’-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 113S: 5’- nnnnnnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 114S: 5’-snnnnmnNfNfNfNfnnmnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 115S: 5’-nNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 116S: 5’-snnnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 117S: 5’- snnnnnNfNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 118S: 5’-snnnnNfnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 119S: 5’-snnnnNfnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 120S: 5’-snnnnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 121S: 5’- nsnsnnnnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 122S: 5’-nsnsnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 123S: 5’-nsnsnnnNfNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 124S: 5’-nsnsnnnNfNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 125S: 5’- nsnsnnNfnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 126S: 5’-nsnsnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 127S: 5’-nsnsnnNfNfnnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 128S: 5’-nsnsnnnnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 129S: 5’-nsnsnnnnnNfNfnnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 130S: 5’- nsnsnnnNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 131S: 5’-nsnsnnNfnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 132S: 5’-nsnsnnNfNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 133S: 5’-nsnsnnnnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 134S: 5’- nsnsnnnNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 135S: 5’-nsnsnnnNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 136S: 5’-nsnsnnnNfNfNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, - 88 - Attorney Docket No.54462-772.601 the sense strand comprises modification pattern 137S: 5’-nsnsnnNfnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 138S: 5’- nsnsnnNfnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 139S: 5’-nsnsnnNfNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 140S: 5’-nsnsnnNfNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 141S: 5’-nsnsnnnnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 142S: 5’-nsnsnnnNfnnNfnnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 143S: 5’- nsnsnnnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 144S: 5’-nsnsnnnnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 145S: 5’-nsnsnnnnNfNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 146S: 5’-nsnsnnnNfnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 147S: 5’- nsnsnnnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 148S: 5’-nsnsnnNfnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 149S: 5’-nsnsnnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 150S: 5’-nsnsnnNfnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 151S: 5’- nsnsnnNfnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 152S: 5’-snnnnnNfNfNfNfnnnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 153S: 5’-snnnnNfndNnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 154S: 5’-snnnnmNfnNfNfNfNfnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 155S: 5’- snnnnmNfnNfNfNfNfnnnnmnnnnnsnsn-3'. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’-deoxy-modified nucleoside or a 2’-deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate. [00179] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5’- nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’- nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3’. In some - 89 - Attorney Docket No.54462-772.601 embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 8AS: 5’-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 11AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13AS: 5'- nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-nsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS: 5'- nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnnNfnnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'- nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'-nsNfsnnnnNfnNfnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS: 5'- nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 23AS: 5'-VPnsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 24AS: 5'-VPnsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 25AS: 5'- VPnsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 26AS: 5'-VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-VPnsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'- nsNfsnnNfnNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 29AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 31AS: 5'- nsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32AS: 5'-nsNfsnnnNfNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense - 90 - Attorney Docket No.54462-772.601 strand comprises modification pattern 36AS: 5'-nsNfsnnnnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37AS: 5'- nsNfsnnNfn[NUNA]nnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38AS: 5'-nsNfsnnNf[NUNA]NfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40AS: 5'- 5VPnsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 41AS: 5'-nnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43AS: 5'- nsNfsnnnNfNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 44AS: 5'-nsNfsnnnNfnnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 45AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 47AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 48AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 49AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfnNfnNfnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 51AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfnNf[UNA]NfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55AS: 5'- nsNfsnnnn[UNA]NfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 56AS: 5’-nsnsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 57AS: 5’‑nsNfsnNfnnNfnnNfnNfnNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’‑nsNfsnnnNfnNfnNfnNfnNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 59AS: 5’‑nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 60AS: 5'-nsNfsnNfnNfnnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61AS: 5'- nsNfsnNfnNfnnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62AS: 5'-nsNfsnNfnnNfnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63AS: 5'-nsNfsnnNfnNfnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64AS: 5'- nsNfsnNfnNfnNfnnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises - 91 - Attorney Docket No.54462-772.601 modification pattern 65AS: 5'-nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66AS: 5'-nsNfsnNfnnNfnNfnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67AS: 5'- nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 68AS: 5'-nsNfsnnNfnNfnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 69AS: 5'-nsNfsnnn[NUNA]nNfnNfnnnNfnNfnnnsnsn-3’. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’-deoxy- modified nucleoside or a 2’-deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification, VP is a 5'- vinyl phosphonate, “[NUNA]” is an unlocked nucleic acid, “[UNA]” is an unlocked nucleic acid and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate. [00180] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, 69AS, 70AS, 71AS, or 72AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, - 92 - Attorney Docket No.54462-772.601 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, - 93 - Attorney Docket No.54462-772.601 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, - 94 - Attorney Docket No.54462-772.601 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, - 95 - Attorney Docket No.54462-772.601 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, - 96 - Attorney Docket No.54462-772.601 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, - 97 - Attorney Docket No.54462-772.601 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the - 98 - Attorney Docket No.54462-772.601 sense strand comprises pattern 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 55S and the antisense - 99 - Attorney Docket No.54462-772.601 strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, - 100 - Attorney Docket No.54462-772.601 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 65S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 66S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 67S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 68S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 69S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, - 101 - Attorney Docket No.54462-772.601 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 70S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 71S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 72S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 73S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 74S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 75S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 76S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, - 102 - Attorney Docket No.54462-772.601 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 77S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 78S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 79S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 80S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 81S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 82S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 83S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, - 103 - Attorney Docket No.54462-772.601 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 84S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 85S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 86S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 87S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 88S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 89S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 90S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, - 104 - Attorney Docket No.54462-772.601 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 91S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 92S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 93S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 94S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 95S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 96S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 97S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, - 105 - Attorney Docket No.54462-772.601 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 98S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 99S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 100S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 101S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 102S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 103S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 104S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or - 106 - Attorney Docket No.54462-772.601 69AS. In some embodiments, the sense strand comprises pattern 105S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 106S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 107S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 108S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 109S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 110S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 111S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some - 107 - Attorney Docket No.54462-772.601 embodiments, the sense strand comprises pattern 112S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 113S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 114S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 115S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 116S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 117S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 118S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the - 108 - Attorney Docket No.54462-772.601 sense strand comprises pattern 119S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 120S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 121S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 122S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 123S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 124S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 125S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense - 109 - Attorney Docket No.54462-772.601 strand comprises pattern 126S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 127S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 128S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 129S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 130S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 131S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 132S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand - 110 - Attorney Docket No.54462-772.601 comprises pattern 133S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 134S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 135S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 136S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 137S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 138S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 139S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises - 111 - Attorney Docket No.54462-772.601 pattern 140S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 141S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 142S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 143S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 144S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 145S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 146S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 147S and the - 112 - Attorney Docket No.54462-772.601 antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 148S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 149S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 150S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 151S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 152S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 153S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 154S and the antisense - 113 - Attorney Docket No.54462-772.601 strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 155S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. [00181] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 1AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern - 114 - Attorney Docket No.54462-772.601 3AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, - 115 - Attorney Docket No.54462-772.601 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S.34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 11AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, - 116 - Attorney Docket No.54462-772.601 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 14AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, - 117 - Attorney Docket No.54462-772.601 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 17AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 18AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 19AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, - 118 - Attorney Docket No.54462-772.601 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 20AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 21AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 22AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 23AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, - 119 - Attorney Docket No.54462-772.601 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 24AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 25AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 26AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 28AS. In some embodiments, the sense strand - 120 - Attorney Docket No.54462-772.601 comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 29AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 30AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 31AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 32AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, - 121 - Attorney Docket No.54462-772.601 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 33AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 34AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 35AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 36AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, - 122 - Attorney Docket No.54462-772.601 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 37AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 39AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 40AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, - 123 - Attorney Docket No.54462-772.601 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 41AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 42AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 43AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 44AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, - 124 - Attorney Docket No.54462-772.601 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 45AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 46AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 47AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 48AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, - 125 - Attorney Docket No.54462-772.601 154S, or 155S, and the antisense strand comprises pattern 49AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 50AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 51AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 52AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 53AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, - 126 - Attorney Docket No.54462-772.601 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 54AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 55AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 56AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 57AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, - 127 - Attorney Docket No.54462-772.601 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, and the antisense strand comprises pattern 58AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 59AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 60AS. [00182] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 61AS. [00183] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, - 128 - Attorney Docket No.54462-772.601 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 62AS. [00184] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, 155S, or 155S and the antisense strand comprises pattern 63AS. [00185] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 64AS. [00186] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 65AS. [00187] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, - 129 - Attorney Docket No.54462-772.601 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 66AS. [00188] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 67AS. [00189] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 68AS. [00190] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S and the antisense strand comprises pattern 69AS. - 130 - Attorney Docket No.54462-772.601 [00191] In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, or 9S. In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. [00192] In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O- - 131 - Attorney Docket No.54462-772.601 methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. [00193] In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise 2’-fluoro modified purines. [00194] In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O- methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2’-fluoro modified purines. [00195] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. - 132 - Attorney Docket No.54462-772.601 [00196] In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. [00197] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O- methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines. [00198] In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise 2’-fluoro modified purines. - 133 - Attorney Docket No.54462-772.601 [00199] Disclosed herein, in some embodiments, are modified oligonucleotides. The modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency. The siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject. The modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression. [00200] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs. In some embodiments, the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand. One strand (antisense strand) is complementary to a PLOD2 mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a PLOD2 mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the PLOD2 mRNA. In some embodiments, there are 1-2 phosphorothioates at the 3’ end. In some embodiments, there are 1 or no phosphorothioates at the 5’ end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached at the 5’ end via a phosphodiester bond. [00201] In some cases, the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern. In some embodiments of the modification pattern, position 9 counting from the 5’ end of the sense strand may have a 2’F modification. In some embodiments, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules. [00202] In some embodiments, when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent - 134 - Attorney Docket No.54462-772.601 positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules. [00203] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules. [00204] Terminal modifications useful for modulating activity include modification of the 5' end of the antisense strand with phosphate or phosphate analogs. In certain embodiments, the 5' end of the antisense strand is phosphorylated or includes a phosphoryl analog. Exemplary 5'-phosphate modifications include those which are compatible with RNA-induced silencing complex (RISC) mediated gene silencing. In some embodiments, the 3' end of the antisense strand is phosphorylated or includes a phosphoryl analog. In some embodiments, the 5' end of the sense strand is phosphorylated or includes a phosphoryl analog. In some embodiments, the 3' end of the sense strand is phosphorylated or includes a phosphoryl analog. [00205] In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 5’ end of the antisense strand. In some embodiment, the phosphate mimic includes a 5'-vinyl phosphonate (VP). In some embodiment, the phosphate mimic is a 5'-VP. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3' end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 5' end of the sense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3' end of the sense strand. [00206] In some embodiments, the sense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the sense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside. The deoxy nucleoside may be at a position within the sense strand (5’ to 3’, where the 5’ position is 1). The position within the sense strand may be or include position 2, 4, 6, 8, 9, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 4, 6, 8, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 9, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 4, 8, 9, 12, or 16, or a combination of said positions. The position within the sense strand may be or include position 4, 8, 12, or 16, or a combination of said positions. The position within the sense strand may include position 9. The position within the sense strand may be position 9. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, - 135 - Attorney Docket No.54462-772.601 16, 17, 18, or 19 deoxy nucleosides. In some embodiments, the sense strand includes 1 deoxy nucleoside. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides. The sense strand may include deoxy nucleosides at all even positions. The sense strand may include deoxy nucleosides at some even positions. The sense strand may include deoxy nucleosides at every other even position. The sense strand may include 1 deoxy nucleoside. The sense strand may include at least 1 deoxy nucleoside. The sense strand may include at least 2 deoxy nucleosides. The sense strand may include at least 3 deoxy nucleosides. The sense strand may include at least 4 deoxy nucleosides. The sense strand may include at least 5 deoxy nucleosides. The sense strand may include at least 6 deoxy nucleosides. The sense strand may include at least 7 deoxy nucleosides. The sense strand may include at least 8 deoxy nucleosides. The sense strand may include at least 9 deoxy nucleosides. The sense strand may include at least 10 deoxy nucleosides. The sense strand may include no greater than 2 deoxy nucleosides. The sense strand may include no greater than 3 deoxy nucleosides. The sense strand may include no greater than 4 deoxy nucleosides. The sense strand may include no greater than 5 deoxy nucleosides. The sense strand may include no greater than 6 deoxy nucleosides. The sense strand may include no greater than 7 deoxy nucleosides. The sense strand may include no greater than 8 deoxy nucleosides. The sense strand may include no greater than 9 deoxy nucleosides. The sense strand may include no greater than 10 deoxy nucleosides. [00207] In some embodiments, the antisense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the antisense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside. The antisense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides. [00208] In some embodiments in which a deoxy nucleoside is included in the sense strand (e.g., at the 9th nucleotide counting from 5’ end), nucleosides at positions 1-8 include a mixture of 2’-fluoro and 2’- O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, nucleosides at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions - 136 - Attorney Docket No.54462-772.601 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and purines at positions 1-8 all include 2’-O-methyl modified nucleosides. [00209] Disclosed herein, in some embodiments are compositions comprising an oligonucleotide that targets PLOD2 and when administered to a cell decreases expression of PLOD2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one internucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the antisense strand sequence in which at least one internucleoside linkage is modified and at least one nucleoside is modified. Some embodiments relate to methods that include administering the composition to a subject. [00210] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- - 137 - Attorney Docket No.54462-772.601 methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’- O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro - 138 - Attorney Docket No.54462-772.601 and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; and wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. [00211] In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro modified and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some - 139 - Attorney Docket No.54462-772.601 embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified. [00212] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 4. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 4. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 4. The siRNA may include some unmodified internucleoside linkages or nucleosides. [00213] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 80% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 85% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, at least 90% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or at least 95% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7464- 7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOS: 7464-7773, 8102-8106, 8140-8149, 8174-8177, or 8190-8191 in PLOD2. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. [00214] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NOS: 7774-8083 in PLOD2, at least 80% identical to SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, at least 85% identical to SEQ ID NOS: 7774-8083 in PLOD2, at least 90% identical to SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178- 8181, or 8192-8193 in PLOD2, or at least 95% identical to SEQ ID NOS: 7774-8083,8107-8111, 8150- 8159, 8178-8181, or 8192-8193 in PLOD2. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NOS: 7774-8083, 8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or - 140 - Attorney Docket No.54462-772.601 consists of the sequence of SEQ ID NOS: 7774-8083,8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2, or an antisense strand sequence thereof having | or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOS: 7774-8083,8107-8111, 8150-8159, 8178-8181, or 8192-8193 in PLOD2. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5'-vinyl phosphonate (VP). [00215] The sense strand or antisense strand may comprise a moiety such as a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Representative example of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative example of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine- glycine-aspartic acid (RGD) peptide. [00216] The siRNA may comprises the sense strand and/or the antisense strand sequence of an siRNA in any table included herein that includes modifications; or may include a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; or may include a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. [00217] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) PLOD2 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset G. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand of subset G, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset G, wherein the nucleotide at the 5’ end of the sense strand - 141 - Attorney Docket No.54462-772.601 sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G. In some embodiments, any of the aforementioned siRNA comprising a sense strand or antisense stand comprises a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense or anti sense strand sequence of one of subset G. The sense strand or antisense stand may comprise a lipid moiety. The sense or antisense strand may comprise a GalNAc moiety. The sense strand or antisense stand may comprise an integrin or an integrin targeting ligand. The sense strand or antisense stand may comprise an angiopep-2. The sense strand or antisense stand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The sense strand or antisense stand may comprise an LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23, L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 13951-14078, thymine (T) may be replaced with uracil (U). [00218] In some embodiments, the sense strand of any of the siRNAs of subset G comprises siRNA with a particular modification pattern. In this modification pattern, position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification. If position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. If position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F - 142 - Attorney Docket No.54462-772.601 modifications in total, provided that the sense strand does not have three 2’F modifications in a row. If position 9 of the sense strand is a purine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. If position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. [00219] In some embodiments, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand. [00220] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. [00221] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. [00222] The oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof. [00223] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- - 143 - Attorney Docket No.54462-772.601 methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’ deoxy nucleoside. [00224] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. [00225] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. 4. ASO modification patterns [00226] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3’, wherein “dN” is any - 144 - Attorney Docket No.54462-772.601 deoxynucleotide, “n” is a 2’-O-methyl or 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate linkage. In some embodiments, the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. D. Formulations [00227] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. [00228] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. In some embodiments, the oligonucleotide is combined with lipids, nanoparticles, polymers, liposomes, micelles, or another delivery system. [00229] In some embodiments, the composition is formulated for delivery to a subject’s osteoarthritic joint (i.e., intra-articularly). In some embodiments, the composition is formulated administration to the joint via topical, transdermal, intradermal, or subcutaneous route. E. Kits [00230] Described herein, in some embodiments, are kits. The kit may include an oligonucleotide such as an siRNA described herein. The oligonucleotide may be conjugated to a lipid moiety or to a sugar moiety. The kit may include a lipid moiety. The kit may include a sugar moiety. The oligonucleotide may comprise nucleoside modifications or modified internucleoside linkages. The oligonucleotide may include any modifications described herein, such as modifications from a base sequence. The kit may include a delivery reagent such as a needle. The kit may comprise a container. The kits may comprise an oligonucleotide such as an siRNA described herein within a pharmaceutically acceptable carrier or - 145 - Attorney Docket No.54462-772.601 diluent. The kits may further comprise excipients. The kit may include instructions for use, such as methods for use in a method described herein. II. METHODS AND USES [00231] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject. [00232] Some embodiments relate to a method of treating a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject. [00233] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject. [00234] Some embodiments relate to a method of preventing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject. [00235] Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject. [00236] Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject. [00237] The administration of a pharmaceutical composition described herein is carried out by any of the many known routes of administration, including intravenously, intra-arterially, subcutaneously, intra- peritoneally or intra-cerebrally, as determined by a skilled practitioner. Using specialized formulations, it is possible to administer the compositions orally or via inhalation or via intranasal instillation. In some - 146 - Attorney Docket No.54462-772.601 embodiments a compound of the present invention is formulated for topical administration, including as eardrops, eye drops, dermal formulation, transdermal formulation and the like. [00238] In some embodiments, the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection. In some embodiments, the administration is to a subject’s osteoarthritic joint. In some embodiments, the administration is intra-articularly. In some embodiments, the administration to the joint is topical, transdermal, intradermal, or subcutaneous route. Administration of the compositions and compounds provided herein can be via any of the accepted modes of administration including, but not limited to, subcutaneous, intravenous, topical, transdermal, intraperitoneal, intramuscular, intrathecal, intra-articular, intracapsular, intraspinal, intrasynovial, epidural, intravascular, or via irrigation of infected bone. In some embodiments, administration is parenteral. In some embodiments, administration is intraarticular. [00239] In some embodiments, the compositions provided herein are administered parenterally, including intramuscularly, intra-articularly, periarticularly, intraspinally, intrasynovially, and epidurally. For example, the compositions can be injected locally at the site of the osteoarthritis (e.g., knee, hip, shoulder, etc.). Injections can occur at one or more locations surrounding the joint. In some embodiments, the injection is guided using an imaging method such as ultrasound. In some embodiments, administration (e.g., injection) of a compound disclosed herein, including amorphous and polymorph forms thereof, is preceded or combined with a local anesthetic. F. Disorders [00240] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder includes an inflammatory disorder. In some embodiments, the disorder is an arthropathy. In some embodiments, the arthropathy includes an osteoarthritis. Non-limiting examples of osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, or degenerative joint disease. In some embodiments, arthropathy leads to arthroplasty, arthroplasty of the hip, arthroplasty of the knee. In some embodiments, the disorder includes a temporomandibular joint (TMJ) disorders. In some embodiments, the disorder includes an arthroplasty. In some embodiments, the disorder includes an arthrosis. In some embodiments, the disorder includes an arthralgia. In some embodiments, the disorder includes a degenerative joint disease. In some embodiments, the disorder includes degradation and/or disruption of cartilage homeostasis. The cartilage homeostasis includes osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, achondroplasia, Paget's disease, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amyloidosis, hydrarthrosis, periodical disease, rheumatoid spondylitis, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. - 147 - Attorney Docket No.54462-772.601 G. Subjects [00241] Some embodiments of the methods described herein include treatment of a subject. Non- limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old). [00242] In some embodiments, the subject has a body mass index (BMI) of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or more. In some embodiments, the subject has a BMI of 25-29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or more. In some embodiments, the subject has a BMI of 30-39. In some embodiments, the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 15-50. [00243] In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is > 90 years of age. In some embodiments, the subject is > 85 years of age. In some embodiments, the subject is > 80 years of age. In some embodiments, the subject is > 70 years of age. In some embodiments, the subject is > 60 years of age. In some embodiments, the subject is > 50 years of age. In some embodiments, the subject is > 40 years of age. In some embodiments, the subject is > 30 years of age. In some embodiments, the subject is > 20 years of age. In some embodiments, the subject is > 10 years of age. In some embodiments, the subject is > 1 years of age. In some embodiments, the subject is > 0 years of age. [00244] In some embodiments, the subject is < 100 years of age. In some embodiments, the subject is < 90 years of age. In some embodiments, the subject is < 85 years of age. In some embodiments, the subject is < 80 years of age. In some embodiments, the subject is < 70 years of age. In some embodiments, the subject is < 60 years of age. In some embodiments, the subject is < 50 years of age. In some embodiments, the subject is <40 years of age. In some embodiments, the subject is < 30 years of age. In some embodiments, the subject is <20 years of age. In some embodiments, the subject is < 10 years of age. In some embodiments, the subject is <1 years of age. [00245] In some embodiments, the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age. - 148 - Attorney Docket No.54462-772.601 [00246] The subject may have a disorder described herein. The subject may have inflammation. The subject may have an inflammatory disease. For example, the subject may have an arthropathy or an osteoarthritis. H. Baseline measurements [00247] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. Non-limiting examples of baseline measurements include a baseline joint function measurement, joint structure measurement, pain measurement, inflammation markers measurement, cartilage biomarkers measurement, bone biomarkers measurement, synovial biomarkers measurement, patient-reported outcome measurement (PROMs), physical function measurement, Quality of life assessment measurement, osteoarthritis flare-up measurement, or a radiographic progression measurement. [00248] In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. [00249] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR. [00250] In some embodiments, the baseline measurement is a joint function measurement. Examples of baseline joint function measurement may include a measurement of range of motion, morning stiffness duration and grip strength. [00251] In some embodiments, the baseline measurement is a joint structure measurement. Examples of baseline joint structure measurement may include a measurement of joint space narrowing, osteophyte formation, subchondral sclerosis, subchondral cyst. Joint space narrowing (JSN) is typically graded using the Osteoarthritis Research Society International (OARSI) atlas criteria, or the Kellgren and Lawrence (K/L) system. The OARSI atlas criteria grades JSN using a 0-3 scale with Grade 0 indicating an absence of JSN, and Grades 1, 2 and 3 indicating mild, moderate, and severe JSN (Altman and Gold, Osteoarthritis Cartilage 2007; 15(Suppl A):A1-A56). The K/L system grades JSN using a 0-4 scale with Grade 0 indicating an absence of JSN, Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 indicating minimal, moderate, and severe JSN (Kellgren and Lawrence, Ann Rheum Dis 1957; 16:494-502). Based on these criteria, OARSI Grade 0 (absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtful presence of JSN). Knee pain in a person having OARSI Grade 0 or K/L Grade or 1 JSN in the knee where the pain occurs may be referred to herein as a “normal joint space knee pain.” - 149 - Attorney Docket No.54462-772.601 [00252] In some embodiments, the baseline measurement is a pain measurement assessed by visual analogue scale (VAS) and WOMAC pain subscale. Commonly used measures of pain intensity include the visual analog scale (VAS) and the numerical rating scale (NRS). With the VAS approach, patients rate the severity of their pain by marking a point on a 10-cm (or 100 mm) VAS (0=no pain and 10=worst possible pain). With the NRS approach, patients rate the severity of their pain by verbally responding to a 10-point NRS (0=no pain and 10=worst possible pain). VAS and NRS scores have been shown to be strongly correlated (slope of regression line, 1.01), indicating that a score on the 10-cm VAS is equivalent to the same score on 10-point NRS (Bijur P E et al. Acad Emerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm) is equivalent to an NRS score of 5. Knee pain in a person with a VAS score of 5 cm or 50 mm or higher, or an NRS score of 5 or higher, may be referred to herein as moderate to severe knee pain. In some embodiments, the person has baseline pain intensity of 5 or greater measured using the 0-10 numerical rating scale (NRS), or 50 mm or greater using the 100 mm visual analog scale (VAS). In some embodiments the person being treated for pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, joint space narrowing. [00253] In some embodiments, the baseline measurement includes an inflammation measurement. In some embodiments, the baseline measurement includes a measurement of inflammation markers. Examples of inflammation markers measurement may include measuring C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, or IL-6. In some embodiments, the baseline measurement includes a measurement of cartilage biomarkers. Examples of cartilage biomarkers measurement may include measuring COMP, aggrecan, type II collagen, proteoglycans, or Hyaluronic acid. In some embodiments, the baseline measurement includes a measurement of bone biomarkers. Examples of bone biomarkers measurement may include measuring CTX-II, NTX-I. In some embodiments, the baseline measurement includes a measurement of synovial biomarkers. Examples of synovial biomarkers measurement may include measuring MMPs, ADAMTS, and the number of pyridinoline cross-links per triple helix collagen. [00254] In some embodiments, the baseline measurement includes patient-reported outcome measures (PROMs) including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In some embodiments, the baseline measurement includes physical function measurement. Examples of physical function measurement may include 6-minute walk test, timed up-and-go test. In some embodiments, the baseline measurement includes quality of life assessments. Examples of quality of life assessments may include SF-36, EQ-5D). In some embodiments, the baseline measurement includes osteoarthritis exacerbations measurement. In some embodiments, the baseline measurement includes radiographic progression measurement assessed by Kellgren-Lawrence grading scale. [00255] In some embodiments, the baseline measurement is a baseline PLOD2 protein measurement. In some embodiments, the baseline PLOD2 protein measurement comprises a baseline PLOD2 protein level. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample weight. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample volume. In some embodiments, the baseline PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per total protein within the - 150 - Attorney Docket No.54462-772.601 sample. In some embodiments, the baseline PLOD2 protein measurement is a baseline circulating PLOD2 protein measurement. In some embodiments, the baseline PLOD2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. [00256] In some embodiments, the baseline measurement is a baseline PLOD2 mRNA measurement. In some embodiments, the baseline PLOD2 mRNA measurement comprises a baseline PLOD2 mRNA level. In some embodiments, the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD23 mRNA per sample weight. In some embodiments, the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample volume. In some embodiments, the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total mRNA within the sample. In some embodiments, the baseline PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total nucleic acids within the sample. In some embodiments, the baseline PLOD2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline PLOD2 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the PLOD2 mRNA. [00257] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject. [00258] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. For example, the baseline PLOD2 protein measurement may be obtained in a fluid sample obtained from the patient. In some embodiments, the baseline PLOD2 mRNA measurement is obtained in a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. A blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. A blood sample may be a serum sample. In some embodiments, the fluid sample includes a synovial fluid sample. In some embodiments, the sample is fractionated or centrifuged. [00259] In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises articular joint, articular cartilage, synovium, synovial membrane. For example, the baseline PLOD2 mRNA measurement, or the baseline PLOD2 protein measurement, may be obtained in a articular joint, articular cartilage, synovium, synovial membrane sample obtained from the patient. - 151 - Attorney Docket No.54462-772.601 [00260] In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell is a chondrocyte. In some embodiments, the cell is a osteoblast. In some embodiments, the cell is a synoviocyte. In some embodiments, the cell is a fibroblast. I. Effects [00261] In some embodiments, the composition or administration of the composition affects a measurement such as osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, Temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, a PLOD2 protein measurement (for example, circulating or tissue PLOD2 protein levels), or a PLOD2 mRNA measurement, relative to the baseline measurement. [00262] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated. [00263] In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample. [00264] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the - 152 - Attorney Docket No.54462-772.601 composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition. [00265] In some embodiments, the composition improves or reduces the measurement relative to the baseline measurement. For example, an adverse phenotype of an arthropathy may be improved or reduced upon administration of the composition. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is reduced by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00266] In some embodiments, the composition improves or increases the measurement relative to the baseline measurement. For example, a protective phenotype of arthropathy may be improved or increased upon administration of the composition. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than - 153 - Attorney Docket No.54462-772.601 about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages. [00267] In some embodiments, the measurement is a joint function measurement. Examples of joint function measurement may include a measurement of range of motion, morning stiffness duration and grip strength. In some embodiments, the composition improves the joint function measurement relative to the baseline joint function measurement. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject. In some embodiments, the joint function measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 10% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 10%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline joint function measurement. In some embodiments, the joint function measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages. [00268] In some embodiments, the measurement is a joint structure measurement. Examples of baseline joint structure measurement may include a measurement of joint space narrowing, osteophyte formation, subchondral sclerosis, subchondral cyst. Joint space narrowing (JSN) is typically graded using the Osteoarthritis Research Society International (OARSI) atlas criteria, or the Kellgren and Lawrence (K/L) system. The OARSI atlas criteria grades JSN using a 0-3 scale with Grade 0 indicating an absence of JSN, and Grades 1, 2 and 3 indicating mild, moderate, and severe JSN (Altman and Gold, Osteoarthritis - 154 - Attorney Docket No.54462-772.601 Cartilage 2007; 15(Suppl A):A1-A56). The K/L system grades JSN using a 0-4 scale with Grade 0 indicating an absence of JSN, Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 indicating minimal, moderate, and severe JSN (Kellgren and Lawrence, Ann Rheum Dis 1957; 16:494-502). Based on these criteria, OARSI Grade 0 (absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtful presence of JSN). Knee pain in a person having OARSI Grade 0 or K/L Grade or 1 JSN in the knee where the pain occurs may be referred to herein as a “normal joint space knee pain.” [00269] In some embodiments, the composition improves the joint structure measurement relative to the baseline joint structure measurement. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject. In some embodiments, the joint structure measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by about 10% or more, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by no more than about 10%, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline joint function measurement. In some embodiments, the joint structure measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline joint structure measurement. In some embodiments, the joint structure measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages. [00270] In some embodiments, the measurement is a pain measurement assessed by visual analogue scale (VAS) and WOMAC pain subscale. Commonly used measures of pain intensity include the visual analog scale (VAS) and the numerical rating scale (NRS). With the VAS approach, patients rate the severity of their pain by marking a point on a 10-cm (or 100 mm) VAS (0=no pain and 10=worst possible pain). With the NRS approach, patients rate the severity of their pain by verbally responding to a 10-point NRS (0=no pain and 10=worst possible pain). VAS and NRS scores have been shown to be strongly correlated (slope of regression line, 1.01), indicating that a score on the 10-cm VAS is equivalent to the same score on 10-point NRS (Bijur P E et al. Acad Emerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm) is equivalent to an NRS score of 5. Knee pain in a person with a VAS score of 5 - 155 - Attorney Docket No.54462-772.601 cm or 50 mm or higher, or an NRS score of 5 or higher, may be referred to herein as moderate to severe knee pain. In some embodiments, the person has baseline pain intensity of 5 or greater measured using the 0-10 numerical rating scale (NRS), or 50 mm or greater using the 100 mm visual analog scale (VAS). In some embodiments the person being treated for pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, joint space narrowing. [00271] In some embodiments, the composition improves the pain measurement relative to the baseline pain measurement. In some embodiments, the improvement is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject. In some embodiments, the pain measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by about 10% or more, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by no more than about 10%, relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline pain measurement. In some embodiments, the pain measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00272] In some embodiments, the measurement includes an inflammation measurement. In some embodiments, the measurement includes a measurement of inflammation markers. Examples of inflammation markers measurement may include measuring C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, or IL-6. In some embodiments, the measurement includes a measurement of cartilage biomarkers. Examples of cartilage biomarkers measurement may include measuring COMP, aggrecan, type I collagen, type II Collagen, proteoglycan or Hyaluronic acid. In some embodiments, the measurement includes a measurement of bone biomarkers. Examples of bone biomarkers measurement may include measuring CTX-II, NTX-I. In some embodiments, the measurement includes a measurement of synovial biomarkers. Examples of synovial biomarkers measurement may include measuring MMPs, ADAMTS, and the number of pyridinoline cross-links per triple helix collagen. In some embodiments, the composition improves the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the improvement is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the inflammation marker - 156 - Attorney Docket No.54462-772.601 measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 10% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 10%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, or no more than about 80%, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement is improved by any of the aforementioned percentages or ranges of percentages, relative to the baseline inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement, or synovial biomarker measurement. [00273] In some embodiments, the measurement includes patient-reported outcome measures (PROMs) including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In some embodiments, the measurement includes a physical function measurement. Examples of physical function measurement may include 6-minute walk test, timed up-and-go test. In some embodiments, the measurement includes quality of life assessments. Examples of quality of life assessments may include SF-36, EQ-5D). In some embodiments, the baseline measurement includes osteoarthritis flare-ups (or - 157 - Attorney Docket No.54462-772.601 exacerbations) measurement. In some embodiments, the baseline measurement includes radiographic progression measurement assessed by Kellgren-Lawrence grading scale. [00274] In some embodiments, the composition improves the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the improvement is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the improvement is measured directly in the subject after administering the composition to the subject. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 10% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 10%, relative to the baseline patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement. In some embodiments, the patient-reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline patient- reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis - 158 - Attorney Docket No.54462-772.601 flare-ups measurement or radiographic progression measurement. In some embodiments, the patient- reported outcome measures, physical function measurement, quality of life assessments, osteoarthritis flare-ups measurement or radiographic progression measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00275] In some embodiments, the measurement is a PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement comprises a PLOD2 protein level. In some embodiments, the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample weight. In some embodiments, the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per sample volume. In some embodiments, the PLOD2 protein level is indicated as a mass or percentage of PLOD2 protein per total protein within the sample. In some embodiments, the PLOD2 protein measurement is a circulating PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is a synovial fluid PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is a tissue PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. [00276] In some embodiments, the composition reduces the PLOD2 protein measurement relative to the baseline PLOD2 protein measurement. In some embodiments, the composition reduces circulating PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the composition reduces synovial fluid PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the composition reduces tissue PLOD2 protein levels relative to the baseline PLOD2 protein measurement. In some embodiments, the reduced PLOD2 protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a blood, serum, plasma, or synovial fluid sample. In some embodiments, the PLOD2 protein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by about 10% or more, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by no more than about 10%, relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline PLOD2 protein measurement. In some embodiments, the PLOD2 protein measurement is reduced by 2.5%, 5%, 7.5%, 19%, 20%, 30%, - 159 - Attorney Docket No.54462-772.601 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00277] In some embodiments, the measurement is a PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement comprises a PLOD2 mRNA level. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample weight. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per sample volume. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total mRNA within the sample or first sample. In some embodiments, the PLOD2 mRNA level is indicated as an amount or percentage of PLOD2 mRNA per total nucleic acids within the sample. In some embodiments, the PLOD2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the PLOD2 mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of the PLOD2 mRNA. [00278] In some embodiments, the composition reduces the PLOD2 mRNA measurement relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces PLOD2 mRNA levels relative to the baseline PLOD2 mRNA levels. In some embodiments, the reduced PLOD2 mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the sample is a synovial fluid sample. In some embodiments, the sample is a tissue sample. In some embodiments, the PLOD2 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by about 10% or more, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by no more than about 10%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline PLOD2 mRNA measurement. In some embodiments, the PLOD2 mRNA measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages. - 160 - Attorney Docket No.54462-772.601 III. DEFINITIONS [00279] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. [00280] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. [00281] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof. [00282] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context. [00283] The terms “subject,” and “patient” may be used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease. [00284] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value. [00285] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is - 161 - Attorney Docket No.54462-772.601 observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. [00286] As used herein, the term "baseline" in reference to an arthropathy-related parameter refers to the value of a patient's arthropathy related parameter before or at the time of administration of a pharmaceutical composition comprising the oligonucleotide such as siRNA as described above. [00287] As used herein, the term "administration" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease. [00288] As used herein, the terms “marker” or “biomarker” as used interchangeably herein refer to any molecule used as a target for analyzing test samples obtained from subjects, and encompass proteins or polypeptides themselves as well as antibodies against same that may be present in a test sample. Proteins or polypeptides used as a marker include any variants and fragments thereof, and in particular, immunologically detectable fragments. For example, it is appreciated that variants of a marker polypeptide are encoded by the same gene, but can differ in their isoelectric point or molecular weight or both as a result of alternative processing such as alternative splicing and/or differences in post- translational modification (e.g., glycosylation, acylation, and/or phosphorylation). It will further be appreciated that cellular proteins can be damaged as a result of a disease process such as inflammation and may fragment and thus that proteins or polypeptides used as a marker according to the present disclosure include fragments thereof. Additionally it will be recognized that certain markers can be synthesized in an inactive form that is subsequently converted to an active form by proteolysis. Proteins or fragments thereof can also occur as part of a complex. Proteins or polypeptides used as markers according to the present disclosure also include such complexes. The terms “biomarker” and “marker” also encompass nucleic acid molecules comprising a nucleotide sequence that codes for a marker protein, and also polynucleotides that can hybridize under stringent conditions with a part of such nucleic acid molecules. [00289] As used herein, the term “sample”, “first sample” or “second sample” generally refers to a biological material being tested for and/or suspected of containing an analyte of interest. The biological material may be derived from any biological source but preferably is a cell, tissue or biological fluid likely to contain the analyte of interest. Examples of biological materials include, but are not limited to, stool, whole blood, serum, plasma, red blood cells, platelets, interstitial fluid, saliva, ocular lens fluid, cerebral spinal fluid, sweat, urine, ascites fluid, mucous, nasal fluid, sputum, synovial fluid, peritoneal fluid, - 162 - Attorney Docket No.54462-772.601 vaginal fluid chondrocytes, osteoblasts, synoviocytes, fibroblasts, articular joint, articular cartilage, synovium, synovial membrane. [00290] As used herein, the term “osteoarthritis” (abbreviated as “OA”), refers to the disease also known as osteoarthrosis and degenerative joint disease, characterized by inflammation and damage to, or loss of cartilage in any joint or joints, and joint pain. Clinical standards for diagnosing osteoarthritis in subjects including mammalian subjects such as canines and humans are well known and include for example swelling or enlargement of joints, joint tenderness or pain, decreased range of motion in joints, visible joint deformities such as bony growths, and crepitus. Symptoms can be identified by clinical observation and history, or imaging including MRI and X-ray. Criteria for diagnosing the presence or absence of OA and severity or degree of OA include but are not limited to the ACR Criteria for knee OA (R. Altman et al., Development of criteria for the classification and reporting of osteoarthritis: Classification of osteoarthritis of the knee: Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. ARTHRITIS RHEUM. August 29(8):1039-1049(1986)), functional status criteria according to WOMAC (N. Bellamy et al., 1988, Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J RHEUMATOL 15:1833-1840), and radiological standards for evaluating OA disease severity according to the Kellgren and Lawrence method for knee OA (Kellgren, J. H. and J. S. Lawrence, Radiological assessment of osteo-arthrosis. ANN RHEUM DIS 16:494-502). [00291] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. [00292] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond. [00293] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane. A bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl. - 163 - Attorney Docket No.54462-772.601 [00294] The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. [00295] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7-dimethyl bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like. [00296] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. [00297] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. [00298] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1- chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein. [00299] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12- membered spiro bicycles, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane. - 164 - Attorney Docket No.54462-772.601 [00300] The term "heteroaryl" refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7- dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6- dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a- octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4 d]pyrimidinyl, pyridinyl, pyrido[3,2 d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3- d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). [00301] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, - 165 - Attorney Docket No.54462-772.601 thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl. [00302] The term "heterocycloalkenyl" refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine. [00303] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. [00304] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N- OH), hydrazino (=N-NH2), -RbORa, -RbOC(O) Ra, -RbOC(O)ORa, -RbOC(O)N(Ra)2, -RbN(Ra)2, - RbC(O)Ra, -RbC(O)ORa, -RbC(O)N(Ra)2, -Rb-ORcC(O)N(Ra)2, -RbN(Ra)C(O)ORa, -RbN(Ra)C(O)Ra, - RbN(Ra)S(O)tRa (where t is 1 or 2), -RbS(O)tRa (where t is 1 or 2), -RbS(O)tORa (where t is 1 or 2), and - RbS(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -RbORa, -RbOC(O)Ra, -RbOC(O)ORa, -RbOC(O)N(Ra)2, -RbN(Ra)2, -RbC(O)Ra, -RbC(O)ORa, - RbC(O)N(Ra)2, -RbORcC(O)N(Ra)2, -RbN(Ra)C(O)ORa, -RbN(Ra)C(O)Ra, -RbN(Ra)S(O)tRa (where t is 1 or - 166 - Attorney Docket No.54462-772.601 2), -RbS(O)tRa (where t is 1 or 2), -RbS(O)tORa (where t is 1 or 2) and -RbS(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -RbORa, -RbOC(O)Ra, -RbOC(O) ORa, -RbOC(O)N(Ra)2, -RbN(Ra)2, -RbC(O)Ra, -RbC(O)ORa, - RbC(O)N(Ra)2, -Rb-ORcC(O)N(Ra)2, -RbN(Ra)C(O)ORa, -RbN(Ra)C(O)Ra, -RbN(Ra)S(O)tRa (where t is 1 or 2), -RbS(O)tRa (where t is 1 or 2), -RbS(O)tORa (where t is 1 or 2), and -RbS(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. [00305] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)”. Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”. [00306] In some embodiments, a "derivative" polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment. A derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label. [00307] Some embodiments refer to nucleic acid sequence information. It is contemplated that in some embodiments, thymine (T) may be interchanged with uracil (U), or vice versa. For example, some sequences in the sequence listing may recite Ts, but these may be replaced with Us in some embodiments. In some oligonucleotides with nucleic acid sequences that include uracil, the uracil may be replaced with thymine. Similarly, in some oligonucleotides with nucleic acid sequences that include thymine, the thymine may be replaced with uracil. In some embodiments, an oligonucleotide such as an siRNA comprises or consists of RNA. In some embodiments, the oligonucleotide may comprise or consist of DNA. For example, an ASO may include DNA. [00308] Some aspects include sequences with nucleotide modifications or modified internucleoside linkages. Generally, and unless otherwise specified, Nf (e.g., Af, Cf, Gf, Tf, or Uf) refers to a 2’-fluoro- modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) refers to a 2’ deoxy nucleoside, n (e.g., a, c, g, t, or u) refers to a 2’-O-methyl modified nucleoside, and “s” refers to a phosphorothioate linkage. [00309] A pyrimidine may include cytosine (C), thymine (T), or uracil (U). A pyrimidine may include C or U. A pyrimidine may include C or T. Where a pyrimidine is referred to, it may indicate a nucleoside or nucleotide comprising a pyrimidine. A purine may include guanine (G) or adenine (A). Where a purine is referred to, it may indicate a nucleoside or nucleotide comprising a purine. [00310] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. - 167 - Attorney Docket No.54462-772.601 IV. EXAMPLES Example 1: Functional Variants in PLOD2 Demonstrate Protective Associations for Osteoarthritis and Related Traits [00311] Genetic variants in PLOD2 were evaluated for associations with traits and diseases related to osteoarthritis in approximately 436,000 individuals with exome sequencing data from the UK Biobank cohort, including a gene burden test aggregating carriers of rare annotated LoF variants in PLOD2 (AAF=0.0003). This gene burden may therefore represent a decrease in the abundance and/or activity of the PLOD2 gene product, and this decrease in the abundance and/or activity may result in the observed genetic associations. [00312] The analyses resulted in identification of associations for the PLOD2 gene burden (Table 2A- 2B). For example, the PLOD2 gene burden was associated with decreased risk of osteoarthritis and osteoarthritis of the knee, and decreased risk of knee replacement surgery (arthroplasty). Table 2A: PLOD2 gene burden associations with osteoarthritis and related traits in UK Biobank Table 2B: PLOD2 gene burden associations with osteoarthritis and related traits in UK Biobank [00313] Genetic variants in PLOD2 were also evaluated for associations with traits and diseases related to osteoarthritis using summary statistics from approximately 412,000 individuals with genotyping data from the FinnGen cohort. Variants evaluated included chr3:146110290:G:C (rs201501322), a rare (AAF=0.002) stop gain variant (S166Ter) in PLOD2 that is predicted to result in a premature truncation of the PLOD2 protein. This variant may therefore represent a decrease in the abundance and/or activity of the PLOD2 gene product, and this decrease in the abundance and/or activity may result in the observed genetic associations. [00314] The analyses resulted in identification of associations for the S166Ter PLOD2 variant (Table 2D-2E). For example, S166Ter was associated with decreased risk of osteoarthritis, osteoarthritis of the hip, hip replacement surgery (arthroplasty), osteoarthritis of the knee, and knee replacement surgery (arthroplasty). Table 2D: PLOD2 variant associations with osteoarthritis and related traits in FinnGen - 168 - Attorney Docket No.54462-772.601 Table 2E: PLOD2 variant associations with osteoarthritis and related traits in FinnGen [00315] These protective associations with putative PLOD2 function- or abundance-decreasing variants across several related and diseases and traits suggest that inhibition of PLOD2 could be therapeutic in these and related traits and diseases. Example 2: Bioinformatic selection of sequences in order to identify therapeutic siRNAs to downmodulate expression of the PLOD2 mRNA [00316] Screening sets were defined based on bioinformatic analysis. Therapeutic siRNAs were designed to target human PLOD2. Predicted specificity in human, rhesus monkey, cynomolgus monkey, mouse, rat, rabbit, and dog was determined for sense (S) and antisense (AS) strands. These were assigned a “specificity score” which considers the likelihood of unintended downregulation of any other transcript by full or partial complementarity of an siRNA strand (up to 2 mismatches within positions 2-18) as well as the number and positions of mismatches. Thus, off-target(s) transcripts for antisense and sense strands of each siRNA were identified. As identified, siRNAs with high specificity and a low number of predicted off-target transcripts provided a benefit of increased targeting specificity. [00317] In addition to selecting siRNA sequences with high sequence specificity to PLOD2 mRNA, siRNA sequences within the seed region were analyzed for similarity to seed regions of known miRNAs. siRNAs can function in a miRNA like manner via base-pairing with complementary sequences within the 3’-UTR of mRNA molecules. The complementarity typically encompasses the 5‘-bases at positions 2-7 of the miRNA (seed region). To circumvent siRNAs to act via functional miRNA binding sites, siRNA strands containing natural miRNA seed regions can be avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit, and pig are referred to as “conserved”. Combining the “specificity score” with miRNA seed analysis yielded a “specificity category”. This is divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of the siRNA is assigned to a specificity category. [00318] Analysis of the Genome Aggregation Database (gnomAD) to identify siRNAs targeting regions with known SNPs was also carried out to identify siRNAs that may be non-functional in individuals containing the SNP. Information regarding the positions of SNPs within the target sequence as well as minor allele frequency (MAF) in case data was obtained in this analysis. [00319] Initial analysis of the relevant PLOD2 mRNA sequence revealed few sequences that fulfil the specificity parameters and at the same time target PLOD2 mRNA in all the analyzed relevant species. Therefore, independent screening subsets were designed for the therapeutic siRNAs. [00320] The siRNAs in these subsets recognized at least the huma PLOD2 sequences. Therefore, the siRNAs in these subsets can be used to target huma PLOD2 in a therapeutic setting. - 169 - Attorney Docket No.54462-772.601 [00321] The number of siRNA sequences derived from huma PLOD2 mRNA (ENST00000282903.10, SEQ ID NO: 1) without consideration of specificity or species cross-reactivity was 3731 (sense and antisense strand sequences included in SEQ ID NOS: 2-3732 and 3733-7463) as shown in Table 3 (listed in Appendix A). [00322] Prioritizing sequences for target specificity, absence of miRNA seed region sequences and SNPs as described above yields subset A. Subset A contains 683 siRNAs whose base sequences are shown in Table 3-Subset A. [00323] The siRNAs in subset A had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; and miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off- target frequency: ≤30 human off-target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ≥ 1% (pos.2-18). [00324] The siRNA sequences in subset A were selected for more stringent specificity to yield subset B. Subset B includes 680 siRNAs whose base sequences are shown in Table 3 subset-B. [00325] The siRNAs in subset B had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off- target frequency: ≤20 human off-target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ≥ 1% (pos.2-18). [00326] The siRNA sequences in subset B were further selected for absence of seed regions in the AS strand that are identical to a seed region of known human miRNA to yield subset C. Subset C includes 470 siRNAs whose base sequences are shown in Table 3 subset-C. [00327] The siRNAs in subset C had the following characteristics: Cross-reactivity: With 19mer in huma PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS strand: seed region not identical to seed region of known human miRNA; Off-target frequency: ≤30 human off-target transcripts with 2 or less mismatches by antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ≥ 1% (pos.2-18). [00328] The siRNA sequences in subset C were also selected for absence of seed regions in the AS or S strands that are identical to a seed region of known human miRNA in addition to having an off-target frequency of ≤30 human off-target transcripts with 2 or less mismatches by antisense strand to yield subset D. Subset D includes 279 siRNAs whose base sequences are shown in Table 3 subset-D. [00329] The siRNA sequences in subset D were also selected to have an off-target frequency of ≤20 human off-target transcripts with 2 or less mismatches by antisense strand to yield subset E. Subset E includes 277 siRNAs whose base sequences are shown in Table 3 subset-E. [00330] Therapeutic siRNAs were designed to target huma PLOD2 as described above and, in some cases, the PLOD2 sequence of at least one toxicology-relevant species, in this case, the non-human primate (NHP) cynomolgus monkey. The siRNAs included in subset F had the following characteristics: - 170 - Attorney Docket No.54462-772.601 [00331] Cross-reactivity: With 19mer in human and cynomolgus monkey PLOD2 mRNA; Specificity category: For human: AS2 or better, SS3 or better; and miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species; Off-target frequency: ≤30 human off- target transcripts with 2 or less mismatches in antisense strand; and SNPs: siRNA target sites do not harbor SNPs with a MAF ≥ 1% (pos.2-18). Sequences were also prioritized for predicted activity. [00332] Subset F includes 310 siRNAs whose base sequences are shown in Table 3 subset-F. [00333] In some cases, the sense strand of any of the siRNAs of subset F comprises siRNA with a particular modification pattern. In this modification pattern, position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification. If position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. If position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. [00334] If position 9 of the sense strand is a purine, then all purines in the sense strand have the 2’OMe modification. If position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with the 2’F modification in the sense strand. If position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with the 2’F modification in the sense strand. If position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. If there are >2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. [00335] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand. [00336] In some cases, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’- fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some - 171 - Attorney Docket No.54462-772.601 embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. [00337] In some cases, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. [00338] The oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof. [00339] In some cases, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O- methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’ deoxy nucleoside. [00340] In some cases, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O- methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro- modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O- methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. [00341] In some cases, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and - 172 - Attorney Docket No.54462-772.601 all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. [00342] In some cases, the sense strand of any of the siRNAs of subset F comprises a modification pattern which conforms to these sense strand rules (Table 3 subset-G, Table 4). [00343] In some cases, the antisense strand of any of the siRNAs Table 3 subset-G, Table 4. TABLE 4. Modified Screening Set - 173 - Attorney Docket No.54462-772.601 - 174 - Attorney Docket No.54462-772.601 - 175 - Attorney Docket No.54462-772.601 - 176 - Attorney Docket No.54462-772.601 - 177 - Attorney Docket No.54462-772.601 [00344] Any siRNA among any of subsets A-E may comprise any modification pattern described herein. If a sequence has a different number of nucleotides in length than a modification pattern, the modification pattern may still be used with the appropriate number of additional nucleotides added 5’ or 3’ to match the number of nucleotides in the modification pattern. For example, if a sense or antisense strand of the siRNA among any of subsets A-E comprises 19 nucleotides, and a modification pattern comprises 21 nucleotides, UU may be added onto the 5’ end of the sense or antisense strand. Example 3: siRNA-mediated Knockdown of PLOD2 in SK-MEL-24 Human Stellate Cell Line [00345] siRNAs targeted to the mRNAs of PLOD2 that downregulate levels of these mRNAs leading to a decrease in expression of these proteins when administered to the cultured human fibroblast cell line, SK-MEL-24. [00346] On Day 0, SK-MEL-24 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No.353047) at 0.5 mL per well. [00347] On Day 1, the PLOD2 siRNAs and negative control siRNA master mixes are prepared. Each siRNA master mix contains 350 µL of Opti-MEM (ThermoFisher Cat. No.31985062) and 3.5 µL of the respective siRNAs (10 µM stock). The negative control siRNA master mix contains 350 µL of Opti-MEM and 3.5 µL of negative control siRNA (ThermoFisher Cat. No.4390843, 10 µM stock). Next, 3 µL of TransIT-X2 (Mirus Cat. No. MIR 6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 50 µL of the appropriate master mix + TransIT-X2 is added to duplicate wells of SK-MEL-24 cells with a final siRNA concentration of 10 nM. [00348] On Day 3, 48 hours post-transfection, media is collected and cells are lysed using the Cells- to-Ct kit according to the manufacturer’s protocol (ThermoFisher Cat. No. AM1728). For the Cells-to-Ct, cells are washed with 50 µL of cold 1X PBS and lysed by adding 50 µL of Lysis Solution and 0.5 µL DNase I per well, pipetting up and down 5 times, and incubating for 5 minutes at room temperature. The Stop Solution (5 µL/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes. The reverse transcriptase reaction is performed using 20 µL of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems) for PLOD2 using a BioRad CFX96 Real-Time System (Cat. No.1855195). [00349] For protein quantification, equivalent quantities (30–50 µg) of protein are separated by 10% SDS polyacrylamide gels and transferred to polyvinylidene fluoride membranes. Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibodies against PLOD2 at dilutions specified by the manufacturer. After washing three times in TBST, the membranes are incubated - 178 - Attorney Docket No.54462-772.601 with the corresponding horseradish peroxidase-conjugated secondary antibody at a 1:5000 dilution for 1 hour. Bound secondary antibody is detected using an enhanced chemiluminescence system. [00350] A decrease in PLOD2 mRNA and protein expression in the SK-MEL-24 cells is expected after transfection with the PLOD2 siRNAs compared to mRNA and protein levels in SK-MEL-24 cells transfected with the non-specific control siRNA 48 hours after transfection. These results indicate that the siRNAs targeting PLOD2 lead to effective knockdown of PLOD2 mRNA in human fibroblast cells and that the decrease in mRNA expression is correlated with a reduction in protein abundance. Example 4: ASO-mediated Knockdown of PLOD2 in SK-MEL-24 Human Stellate Cell Line [00351] ASOs targeted to the mRNAs of PLOD2 that downregulate levels of these mRNAs, leading to a decrease in expression of these proteins when administered to the cultured human fibroblast cell line, SK-MEL-24. [00352] On Day 0, SK-MEL-24 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No.353047) at 0.5 mL per well. [00353] On Day 1, the PLOD2 ASOs and negative control ASO master mixes are prepared. Each ASO master mix contains 350 µL of Opti-MEM (ThermoFisher Cat. No.31985062) and 3.5 µL of the respective ASOs (10 µM stock). The negative control ASO master mix contains 350 µL of Opti-MEM and 3.5 µL of negative control ASO (ThermoFisher Cat. No.4390843, 10 µM stock). Next, 3 µL of TransIT-X2 (Mirus Cat. No. MIR6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 50 µL of the appropriate master mix + TransIT-X2 is added to duplicate wells of SK-MEL-24 cells with a final ASO concentration of 10 nM. [00354] On Day 3, 48 hours post-transfection, media is collected and cells are lysed using the Cells- to-Ct kit according to the manufacturer’s protocol (ThermoFisher Cat. No. AM1728). For the Cells-to-Ct, cells are washed with 50 µL of cold 1X PBS and lysed by adding 50 µL of Lysis Solution and 0.5 µL DNase I per well, pipetting up and down 5 times, and incubating for 5 minutes at room temperature. The Stop Solution (5 µL/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes. The reverse transcriptase reaction is performed using 20 µL of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems) for PLOD2 using a BioRad CFX96 Real-Time System (Cat. No.1855195). [00355] For protein quantification, equivalent quantities (30–50 µg) of protein are separated by 10% SDS polyacrylamide gels and transferred to polyvinylidene fluoride membranes. Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibodies against PLOD2 at dilutions specified by the manufacturer. After washing three times in TBST, the membranes are incubated with the corresponding horseradish peroxidase-conjugated secondary antibody at a 1:5000 dilution for 1 hour. Bound secondary antibody is detected using an enhanced chemiluminescence system. [00356] A decrease in PLOD2 mRNA and protein expression in the SK-MEL-24 cells is expected after transfection with the PLOD2 ASOs compared to mRNA and protein levels in SK-MEL-24 cells transfected with the non-specific control ASO 48 hours after transfection. These results indicate that the - 179 - Attorney Docket No.54462-772.601 ASOs targeting PLOD2 lead to effective knockdown of PLOD2 mRNA in human fibroblast cells and that the decrease in mRNA expression is correlated with a reduction in protein abundance. Example 5: Determining the activity of GalNAc-conjugated siRNAs targeting human PLOD2 mRNA in mice transfected with AAV8-TBG-h-Gluc-PLOD2 [00357] This experiment evaluates GalNAc-conjugated modified siRNAs targeted to the human PLOD2 mRNA when administered to mice transfected with AAV8 vectors encoding the human PLOD2 gene fused with Gaussia princeps luciferase. [00358] Six- to eight-week-old female mice (C57Bl/6) are utilized in this study, with n=8 mice/group. On Study Day -14, all animals are injected via the retroorbital route with 30 uL of a recombinant adeno- associated virus 8 (AAV8) vector (1 x 10^13 genome copies/mL). Separate recombinant AAV8 constructs are prepared, each containing a fusion of the synthetic construct gene for the secreted Gaussia princeps luciferase (NCBI GenBank: LC150601.1) upstream of the open reading frame and parts of the 5’ and 3’ UTRs of the human PLOD2 sequences under the control of the human thyroxine-binding globulin promoter in an AAV2 backbone packaged in an AAV8 capsid. The constructs are designed to encode different fragments of each target transcript under investigation. [00359] On Study Day 0, one group of infected mice is injected subcutaneously with 100 µL of sterile PBS as a control. Other groups are subcutaneously injected with 200 µg of siRNAs specifically targeting human PLOD2, each formulated in 100 µL PBS. The siRNAs are attached to the GalNAc ligand ETL17. Prior to subcutaneous dosing on Study Day 0, all animals are anesthetized, and blood is collected via the submandibular vein puncture to collect plasma. [00360] Luciferase activity is quantified using the Gluc GLOW Assay (Nanolight Cat. No.320) according to the manufacturer’s instructions and represents the amount of each target gene fragment transcript produced along with the luciferase transcript. A reduction in luciferase activity indicates a successful reduction in the respective transcript due to siRNA-mediated gene silencing. [00361] On Study Day 14, animals from all groups are anesthetized, bled via cardiac puncture to collect serum and plasma, and then euthanized. A liver sample is collected from all animals and placed in RNAlater Stabilization Solution (Thermo Fisher, Catalog# AM7020). Serum clinical chemistry analyses are performed (IDEXX Laboratories, Test# 60513) and Gaussia luciferase activity, acting as a proxy for the transcript levels of PLOD2, is measured as described for the Study Day 0 samples. The liver samples are processed in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using the Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, Cat. No. P000933-LYSK0-A) in a Precellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles. Total RNA from the liver lysate is purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA is performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of liver PLOD2 mRNA are assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays designed specifically for human PLOD2 (ThermoFisher), along with the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g1) and PerfeCTa® qPCR FastMix®, - 180 - Attorney Docket No.54462-772.601 Low ROX™ (VWR, Catalog# 101419-222). Data are normalized to the mean mRNA level of PLOD2 in control animals receiving PBS using the delta-delta Ct method. [00362] A decrease in human PLOD2 mRNA expression in the liver of mice transfected with AAV8- TBG-h-Gluc-PLOD2 is expected after treatment with the PLOD2 siRNAs, compared to the mRNA levels in control mice treated with PBS. In animals treated with siRNAs specifically targeting human PLOD2, there is an expected decrease in the relative Gaussia princeps luciferase activity corresponding to reduced expression levels of respective PLOD2 transcripts on Study Day 14 compared with Study Day 0. These results are anticipated to show that the siRNAs targeting human PLOD2 effectively induce knockdown of PLOD2 mRNA in the livers of treated mice transfected with the corresponding AAV8 constructs, and that the decrease in mRNA expression is correlated with a decrease in luciferase activity when fused to parts of the respective transcripts. Example 6: Determining the activity of siRNAs targeting PLOD2 mRNA administered via intra- articular injection in mice [00363] This experiment evaluates ETL20-conjugated modified siRNAs targeting PLOD2, aiming to downregulate PLOD2 mRNA levels in the joint and consequently reduce PLOD2 protein abundance when administered to mice via intra-articular injection. [00364] Six- to eight-week-old female C57BL/6 mice are used in this study, with each group consisting of eight mice. On Day 0, mice are divided into four groups: one group receives intra-articular injection with 10 µL of sterile PBS as a control, while the other three groups receive intra-articular treatments with modified siRNAs specifically targeting mouse PLOD2. Mice receive their respective treatments via delivery through a syringe of 10 µL siRNA (100 ^g in PBS) directly into the knee joint. [00365] Prior to dosing, all animals are acclimated and their baseline joint function and mobility are assessed to ensure health and normal joint function. Post-treatment, joint function is monitored to ensure safety and to assess any immediate effects of the siRNA treatment. [00366] On Day 14 post-treatment, mice from all groups are euthanized. Joint samples, including synovial fluid, tissue and cartilage, are harvested from all animals immediately following euthanasia and placed in RNAlater Stabilization Solution (Thermo Fisher, Catalog# AM7024) to preserve RNA integrity. The joint samples are then processed in homogenization buffer using the Soft Tissue Homogenizing Kit CK14 (Bertin Instruments, Cat. No. P000933-LYSK0-A) in a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles. Total RNA from the joint lysate is purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Preparation of cDNA is performed using Quanta qScript cDNA SuperMix (VWR, Catalog# 95048-500) according to the manufacturer’s instructions. The relative levels of joint PLOD2 mRNA are assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using specific TaqMan assays designed for mouse PLOD2, with normalization to the housekeeping gene PPIA (Thermo Fisher, Assay# Mm02342430_g1) to ensure accuracy in quantification and to control for sample input variation. [00367] Additionally, joint tissue samples are analyzed for PLOD2 protein levels through Western blotting, providing a correlation between the decrease in mRNA levels and the resultant impact on protein - 181 - Attorney Docket No.54462-772.601 expression. These analyses confirm the effectiveness of the siRNA in reducing PLOD2 expression in the joint tissue. [00368] The expected outcome of this study is a significant reduction in both mRNA and protein levels of PLOD2 in the joints of mice treated with PLOD2 siRNAs compared to those treated with the PBS control. Example 7: Inhibition of PLOD2 in a Rat Model for Osteoarthritis Using Modified siRNAs and ASOs [00369] This experiment investigates the role of PLOD2 in osteoarthritis using a rat model where surgical destabilization of the medial meniscus (DMM) simulates joint degradation similar to human osteoarthritis. The experiment will use modified siRNAs and ASOs targeted to the mRNAs of rat PLOD2 individually to modulate their expression and evaluate the effects on joint health and function. The siRNAs and ASOs are attached to the ETL20 ligand for targeted delivery. [00370] DMM surgery is performed on 12-week-old female Sprague-Dawley rats to induce an osteoarthritis-like condition. Sham-operated rats serve as controls. Four weeks post-DMM, rats are divided into six groups of n=10 each, including: Group 1 (sham operated rats treated with vehicle), Group 2 (post-DMM rats treated with vehicle), Group 3 (post-DMM rats treated with non-targeting control siRNA), Group 4 (post-DMM rats treated with non-targeting control ASO), Groups 5 and 6 (post-DMM rats treated with PLOD2-targeting siRNA or ASO). [00371] Rats in groups 3-6 receive their respective treatments via intra-articular injection of 50µl of siRNA/ASO solution (100 ^g in PBS) on Study Day 28, with subsequent doses administered weekly for a total of six treatments. Rats in groups 1 and 2 receive an equivalent volume of vehicle. [00372] Joint health is assessed biweekly using optical coherence tomography (OCT) to visualize cartilage and bone structure, along with pain response measurements (weight-bearing asymmetry and von Frey filament testing) to assess functional outcomes. [00373] Blood samples are collected at baseline and then biweekly post-treatment. Key serum markers of inflammation and cartilage degradation—such as C-reactive protein (CRP), COMP (Cartilage Oligomeric Matrix Protein), and MMPs (Matrix Metalloproteinases)—are measured using standard clinical chemistry analyzers or ELISA. [00374] At the study's conclusion (10 weeks post-DMM), rats are euthanized, and blood, synovial fluid, and joint tissues are collected. Joint samples undergo histological analyses to assess cartilage damage, synovitis, and osteophyte formation using standardized scoring systems. Tissues collected for RNA and protein studies are processed using flash frozen and appropriate extraction kits for subsequent qPCR and Western blot analyses, aiming to confirm the expression levels of PLOD2 mRNA and protein and correlate these with observed phenotypic changes. [00375] The expected results include a demonstration of the efficacy of PLOD2 siRNA/ASO in modulating the expression of these genes, with concomitant improvements in joint health, as evidenced by OCT, functional assessments, serum biomarkers, and histological analyses of joint tissues. These findings are anticipated to reflect the therapeutic potential of inhibiting PLOD2 in the treatment of osteoarthritis. - 182 - Attorney Docket No.54462-772.601 Example 8: Intra-articular delivery of siRNAs into rats [00376] 4-7 week old Sprague Dawley rats (Envigo Labs) rats (n=3) were injected intra-articularly with 50 μL of 4 mg/ml of ETD03580-ETD03584 or PBS per joint. On Day 14, the rats were euthanized and samples of joints were harvested by cutting approximately 5 mm above and below joint and after removal of hair and skin from each animal and placed in RNAlater (ThermoFisher Cat#AM7020). Total RNA was prepared by homogenizing tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for ten to fifteen cycles of 10 second duration. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. Samples with poor RNA yield were excluded from analysis. The levels of PLOD2 mRNA in each joint were assessed by RT-qPCR using TaqMan assays for rat PLOD2 (Cat # Rn00598533_m1) and the rat housekeeping gene PPIA (Cat # Rn00690933_m1) (Table 7). Data were normalized to the level in animals receiving vehicle (PBS). The siRNAs injected are depicted in Tables 5 and 6. Table 5: Base siRNA sequences Table 6: Modified siRNA sequences - 183 - Attorney Docket No.54462-772.601 Table 7. Relative mRNA expression Example 9: Screening of siRNAs ETD03672-ETD03676 and ETD03683-ETD03687 targeting human PLOD2 mRNA in mice transfected with AAV8-Gluc-hPLOD2 [00377] The siRNAs are conjugated to the GalNAc ligand ETL17. The activities of siRNAs, namely ETD03672-ETD03676 and ETD03683-ETD03687, were assessed in mice transiently expressing human PLOD2. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNA sequences that were used are shown in Table 9, where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’-fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage. The base sequences for each siRNA, without the 3’ UU extension, are shown in Table 8. [00378] Six- to eight-week-old female mice (C57Bl/6) were injected with 10 μL of a recombinant adeno-associated virus 8 (AAV8) vector (5.06 x 1013 genome copies/mL) and 20 μL of PBS for a total 30 μL injection volume by the retroorbital route on Day -15. The recombinant AAV8 contains the Gaussia luciferase (GLuc) tag and positions 1-2000 of the open reading frame of the human PLOD2 sequence (ENST00000282903.10) under the control of the human thyroxine binding globulin (TBG) promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-Gluc-hPLOD2_f1_1-2000:oPRE). Circulating levels of the secreted GLuc were measured in plasma by a GLuc GLOW assay (Nanolight Technology, #320-50). Briefly, recombinant Gaussia luciferase protein was diluted in a series to create a standard curve. Whole blood was collected from mice injected with AAV8, processed to plasma, and diluted 1:10 in the GLOW assay buffer. The standard curve and samples were then incubated with coelenterazine substrate for 5 minutes then luminescence was measured on a plate reader (Perkin Elmer). Samples were interpolated based on the standard curve values for plasma GLuc concentration. The mice were allocated into groups with similar average GLuc levels. [00379] On Day 0, infected mice were given a subcutaneous injection of a single 100 µg dose of a GalNAc-conjugated siRNA or PBS as vehicle control (n =4). Mice were bled on Day 10 after subcutaneous - 184 - Attorney Docket No.54462-772.601 injection with whole blood processed to plasma. GLuc levels in the plasma were measured with GLuc GLOW assay and normalized relative to the PBS control group. Results are shown in Table 10. Table 8: Base siRNA sequences Table 9: Modified siRNA sequences - 185 - Attorney Docket No.54462-772.601 Table 10. Relative GLuc expression Example 10: Screening of human and rat PLOD2 cross-reactive siRNAs ETD03674, ETD03676, ETD03679-ETD03683 in rats [00380] Several siRNAs designed to be cross-reactive with human and rat PLOD2 mRNA were tested for activity in rats. The siRNAs are conjugated to the GalNAc ligand ETL17. The activities of siRNAs, namely ETD03674, ETD03676, and ETD03679-ETD03683, were assessed in rats. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNA sequences that were used are shown in Table 12, where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’- fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage. The base sequences for each siRNA, without the 3’ UU extension, are shown in Table 11. [00381] On Day 0, 4-7 week old Sprague Dawley rats (Envigo Labs) rats (n=4) were given a subcutaneous injection with 200 μL of 5 mg/ml of ETD03674, ETD03676, and ETD03679-ETD03683 or PBS as vehicle control. On Day 14, the rats were euthanized and a tissue punch from the left lobe of the liver was collected from each animal and placed in RNAlater (ThermoFisher Cat#AM7020). Total RNA was prepared by homogenizing tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for ten to fifteen cycles of 10 second duration. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations. The levels of PLOD2 mRNA were assessed by RT-qPCR using TaqMan assays for rat PLOD2 (Cat# Rn00598533_m1) and the rat housekeeping gene PPIA (Cat# Rn0690933_m1) (Table 13). Data were normalized to the level in animals receiving vehicle (PBS). The siRNAs injected are depicted in Tables 11 and 12. Table 11: Base siRNA sequences - 186 - Attorney Docket No.54462-772.601 Table 12: Modified siRNA sequences Table 13. Relative mRNA expression Example 11: Screening of siRNAs ETD03676-ETD03682 targeting human PLOD2 mRNA in mice transfected with AAV8-Gluc-hPLOD2 [00382] The siRNAs are conjugated to the GalNAc ligand ETL17. The activities of siRNAs, namely ETD03676-ETD03682, were assessed in mice transiently expressing human PLOD2. The siRNAs contain the GalNAc ligand ETL17 followed by a phosphorothioate linkage at the 5’ end of the sense strand. The siRNA sequences that were used are shown in Tables 9, 12, and 15 where Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2’-fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2’-O-methyl modified nucleoside, dN (e.g., dA, dC, dG, dT, or dU) is a 2' deoxynucleoside, [NUNA] is an unlocked nucleoside and “s” is a phosphorothioate linkage. The base sequences for each siRNA, without the 3’ UU extension, are shown in Table 8, 11, and 14. [00383] Six- to eight-week-old female mice (C57Bl/6) were injected with 10 μL of a recombinant adeno-associated virus 8 (AAV8) vector (4.32 x 1013 genome copies/mL) and 20 μL of PBS for a total 30 μL injection volume by the retroorbital route on Day -15. The recombinant AAV8 contains the Gaussia luciferase (GLuc) tag and positions 1800-3749 of the open reading frame of the human PLOD2 sequence (ENST00000282903.10) under the control of the human thyroxine binding globulin (TBG) promoter in an - 187 - Attorney Docket No.54462-772.601 AAV2 backbone packaged in AAV8 capsid (AAV8-Gluc-hPLOD2_f2_1800-3749:oPRE). Circulating levels of the secreted GLuc were measured in plasma by a GLuc GLOW assay (Nanolight Technology, #320-50). Briefly, recombinant Gaussia luciferase protein was diluted in a series to create a standard curve. Whole blood was collected from mice injected with AAV8, processed to plasma, and diluted 1:10 in the GLOW assay buffer. The standard curve and samples were then incubated with coelenterazine substrate for 5 minutes then luminescence was measured on a plate reader (Perkin Elmer). Samples were interpolated based on the standard curve values for plasma GLuc concentration. The mice were allocated into groups with similar average GLuc levels. [00384] On Day 0, infected mice were given a subcutaneous injection of a single 100 µg dose of a GalNAc-conjugated siRNA or PBS as vehicle control (n =4). Mice were bled on Day 12 after subcutaneous injection with whole blood processed to plasma. GLuc levels in the plasma were measured with GLuc GLOW assay and normalized relative to the PBS control group. Results are shown in Table 16. Table 14: Base siRNA sequences Table 15: Modified siRNA sequences Table 16. Relative GLuc expression Example 12: Protective variants in PLOD2 result in altered cellular protein levels of PLOD2 [00385] The cDNA of PLOD2 protein-coding transcript ENST00000282903.10 was cloned into the pcDNA3.1(+) DNA expression vector driven by a constitutive CMV promoter. A representative variant - 188 - Attorney Docket No.54462-772.601 from the osteoarthritis-protective PLOD2 gene burden test (R495Ter, chr3:146079133:G:A) was selected for evaluation, together with the S166Ter (chr3:146110290:G:C) variant. N-terminus FLAG-tagged PLOD2 WT (wild-type), R495Ter and S166Ter constructs were generated. [00386] Lipid-based plasmid transfection of human embryonic kidney 293T (HEK293T) cells was used to generate samples to test the expression consequence of PLOD2 variants.1x104 HEK293T cells were plated in a 96-well dish with DMEM + 10% FBS and grown for 24 hours. Cells were then transfected with 0.10 µg of each plasmid DNA and 0.20 µl of Lipofectamine-2000 per well of the 96-well plate (a mock-transfected well including Lipofectamine-2000 reagent in the absence of DNA was included as a control).72-hours post-transfection, RNA or protein was harvested from respective individual wells. Transfections and analyses were done in biological triplicate. [00387] Whole cell protein lysates or cell culture media supernatants from transfected cells were evaluated for respective intracellular and extracellular PLOD2 protein by western blot (FIG.1). In Empty vector transfected HEK293T cells, PLOD2 was not detectable using anti-FLAG detection antibodies. In cells transfected with WT DNA constructs, PLOD2 was detected by western blot as a band of ~90 kDa using anti-FLAG detection antibodies. In cells transfected with the S166Ter stop gain variant DNA construct, intracellular PLOD2 was detected as a truncated protein of the predicted molecular weight of ~19 kDa with reduced levels compared to WT, and extracellular PLOD2 was undetectable by western blot using anti-FLAG antibodies. In cells transfected with the R495Ter variant DNA construct, intracellular PLOD2 showed a truncated protein of the predicted molecular weight of ~60 kDa with similar levels to WT, and extracellular PLOD2 was undetectable using the anti-FLAG antibody. [00388] These data provide experimental verification that osteoarthritis-protective genetic variants in PLOD2 result in a decrease in PLOD2 protein levels consistent with a loss-of-function phenotype. These data suggest that in some cases, therapeutic inhibition or modulation of PLOD2 may be an effective genetically-informed method of treatment for osteoarthritis and related diseases. [00389] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and compositions within the scope of these claims and their equivalents be covered thereby. V. SEQUENCE INFORMATION [00390] Some embodiments include one or more nucleic acid sequences in the following tables: Table 17. Sequence Information - 189 - Attorney Docket No.54462-772.601 - 190 - Attorney Docket No.54462-772.601 - 191 - Attorney Docket No.54462-772.601 APPENDIX A Table 3: All siRNA sequences derived from human PLOD2 mRNA - 192 - Attorney Docket No.54462-772.601 - 193 - Attorney Docket No.54462-772.601 - 194 - Attorney Docket No.54462-772.601 - 195 - Attorney Docket No.54462-772.601 - 196 - Attorney Docket No.54462-772.601 - 197 - Attorney Docket No.54462-772.601 - 198 - Attorney Docket No.54462-772.601 - 199 - Attorney Docket No.54462-772.601 - 200 - Attorney Docket No.54462-772.601 - 201 - Attorney Docket No.54462-772.601 - 202 - Attorney Docket No.54462-772.601 - 203 - Attorney Docket No.54462-772.601 - 204 - Attorney Docket No.54462-772.601 - 205 - Attorney Docket No.54462-772.601 - 206 - Attorney Docket No.54462-772.601 - 207 - Attorney Docket No.54462-772.601 - 208 - Attorney Docket No.54462-772.601 - 209 - Attorney Docket No.54462-772.601 - 210 - Attorney Docket No.54462-772.601 - 211 - Attorney Docket No.54462-772.601 - 212 - Attorney Docket No.54462-772.601 - 213 - Attorney Docket No.54462-772.601 - 214 - Attorney Docket No.54462-772.601 - 215 - Attorney Docket No.54462-772.601 - 216 - Attorney Docket No.54462-772.601 - 217 - Attorney Docket No.54462-772.601 - 218 - Attorney Docket No.54462-772.601 - 219 - Attorney Docket No.54462-772.601 - 220 - Attorney Docket No.54462-772.601 - 221 - Attorney Docket No.54462-772.601 - 222 - Attorney Docket No.54462-772.601 - 223 - Attorney Docket No.54462-772.601 - 224 - Attorney Docket No.54462-772.601 - 225 - Attorney Docket No.54462-772.601 - 226 - Attorney Docket No.54462-772.601 - 227 - Attorney Docket No.54462-772.601 - 228 - Attorney Docket No.54462-772.601 - 229 - Attorney Docket No.54462-772.601 - 230 - Attorney Docket No.54462-772.601 - 231 - Attorney Docket No.54462-772.601 - 232 - Attorney Docket No.54462-772.601 - 233 - Attorney Docket No.54462-772.601 - 234 - Attorney Docket No.54462-772.601 - 235 - Attorney Docket No.54462-772.601 - 236 - Attorney Docket No.54462-772.601 - 237 - Attorney Docket No.54462-772.601 - 238 - Attorney Docket No.54462-772.601 - 239 - Attorney Docket No.54462-772.601 - 240 - Attorney Docket No.54462-772.601 - 241 - Attorney Docket No.54462-772.601 - 242 - Attorney Docket No.54462-772.601 - 243 - Attorney Docket No.54462-772.601 - 244 - Attorney Docket No.54462-772.601 - 245 - Attorney Docket No.54462-772.601 - 246 - Attorney Docket No.54462-772.601 - 247 - Attorney Docket No.54462-772.601 - 248 - Attorney Docket No.54462-772.601 - 249 - Attorney Docket No.54462-772.601 - 250 - Attorney Docket No.54462-772.601 - 251 - Attorney Docket No.54462-772.601 - 252 - Attorney Docket No.54462-772.601 - 253 - Attorney Docket No.54462-772.601 - 254 - Attorney Docket No.54462-772.601 - 255 - Attorney Docket No.54462-772.601 - 256 - Attorney Docket No.54462-772.601 - 257 - Attorney Docket No.54462-772.601 - 258 - Attorney Docket No.54462-772.601 - 259 - Attorney Docket No.54462-772.601 - 260 - Attorney Docket No.54462-772.601 - 261 - Attorney Docket No.54462-772.601 - 262 - Attorney Docket No.54462-772.601 - 263 - Attorney Docket No.54462-772.601 - 264 - Attorney Docket No.54462-772.601 - 265 - Attorney Docket No.54462-772.601 - 266 - Attorney Docket No.54462-772.601 - 267 - Attorney Docket No.54462-772.601 - 268 - Attorney Docket No.54462-772.601 - 269 - Attorney Docket No.54462-772.601 - 270 - Attorney Docket No.54462-772.601 - 271 - Attorney Docket No.54462-772.601 - 272 - Attorney Docket No.54462-772.601 - 273 - Attorney Docket No.54462-772.601 - 274 - Attorney Docket No.54462-772.601 - 275 - Attorney Docket No.54462-772.601 - 276 - Attorney Docket No.54462-772.601 - 277 - Attorney Docket No.54462-772.601 - 278 - Attorney Docket No.54462-772.601 - 279 - Attorney Docket No.54462-772.601 - 280 - Attorney Docket No.54462-772.601 - 281 - Attorney Docket No.54462-772.601 - 282 - Attorney Docket No.54462-772.601 - 283 - Attorney Docket No.54462-772.601 - 284 - Attorney Docket No.54462-772.601 - 285 - Attorney Docket No.54462-772.601 - 286 - Attorney Docket No.54462-772.601 - 287 - Attorney Docket No.54462-772.601 - 288 - Attorney Docket No.54462-772.601 - 289 - Attorney Docket No.54462-772.601 - 290 - Attorney Docket No.54462-772.601 - 291 - Attorney Docket No.54462-772.601 - 292 - Attorney Docket No.54462-772.601 - 293 - Attorney Docket No.54462-772.601 - 294 - Attorney Docket No.54462-772.601 - 295 - Attorney Docket No.54462-772.601 - 296 - Attorney Docket No.54462-772.601 - 297 - Attorney Docket No.54462-772.601 - 298 - Attorney Docket No.54462-772.601 - 299 - Attorney Docket No.54462-772.601 - 300 - Attorney Docket No.54462-772.601 - 301 - Attorney Docket No.54462-772.601 - 302 - Attorney Docket No.54462-772.601 - 303 - Attorney Docket No.54462-772.601 - 304 - Attorney Docket No.54462-772.601 - 305 - Attorney Docket No.54462-772.601 - 306 - Attorney Docket No.54462-772.601 - 307 - Attorney Docket No.54462-772.601 - 308 - Attorney Docket No.54462-772.601 - 309 - Attorney Docket No.54462-772.601 - 310 - Attorney Docket No.54462-772.601 - 311 - Attorney Docket No.54462-772.601 - 312 - Attorney Docket No.54462-772.601 - 313 - Attorney Docket No.54462-772.601 - 314 - Attorney Docket No.54462-772.601 - 315 - Attorney Docket No.54462-772.601 - 316 -

Claims

Attorney Docket No.54462-772.601 CLAIMS What is claimed is: 1. A composition comprising an oligonucleotide that targets PLOD2 and when administered to a subject in an effective amount treats an arthropathy. 2. The composition of claim 1, wherein the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof. 3. The composition of claim 1, wherein the treatment of the arthropathy results in, or is intended for, the prevention of arthroplasty, prevention of arthroplasty of the hip, prevention of arthroplasty of the knee, or a combination thereof. 4. The composition of claim 1, wherein the effective amount of the oligonucleotide improves: (a) a joint function measurement; (b) a joint structure measurement; (c) a pain measurement; (d) an inflammation marker measurement, cartilage biomarker measurement, bone biomarker measurement or synovial biomarker measurement; or (e) an osteoarthritis flare-up measurement. 5. The composition of claim 4, wherein the joint function measurement comprises range of motion measurement, morning stiffness duration, or grip strength measurement. 6. The composition of claim 4, wherein the joint function measurement is improved by about 10% or more, as compared to prior to administration. 7. The composition of claim 4, wherein the joint structure measurement comprises a joint space narrowing, osteophyte formation, subchondral sclerosis measurement, or subchondral cyst measurement. 8. The composition of claim 4, wherein the joint structure measurement is improved by about 10% or more, as compared to prior to administration. 9. The composition of claim 4, wherein the inflammation marker measurement comprises a C- reactive protein measurement (CRP), erythrocyte sedimentation rate (ESR) measurement, interleukin (IL)- 1β, tumor necrosis factor (TNF)-α, or IL-6 measurement, or a combination thereof. 10. The composition of claim 4, wherein the cartilage biomarker measurement comprises a cartilage oligomeric matrix protein (COMP) measurement, aggrecan measurement, type I collagen measurement, type II collagen measurement, proteoglycan measurement, hyaluronic acid measurement, or a combination thereof. 11. The composition of claim 4, wherein the inflammation marker measurement is improved by about 10% or more, as compared to prior to administration. 12. The composition of claim 4, wherein the cartilage biomarker measurement is improved by about 10% or more, as compared to prior to administration. - 317 - Attorney Docket No.54462-772.601 13. The composition of claim 4, wherein the bone biomarkers measurement comprises a type II collagen telopeptide fragments (CTX-II) measurement, type I collagen N-telopeptide (NTX-I) measurement, or a combination thereof. 14. The composition of claim 4, wherein the bone biomarker measurement is improved by about 10% or more, as compared to prior to administration. 15. The composition of claim 4, wherein the synovial biomarkers measurement comprises a MMP (matrix metalloproteinases) measurement, A Disintegrin And Metalloprotease with Thrombospondin motifs (ADAMTS) measurement, a number of pyridinoline cross-links per triple helix collagen measurement, or a combination thereof. 16. The composition of claim 4, wherein the synovial biomarker measurement is improved by about 10% or more, as compared to prior to administration. 17. The composition of any one of claims 1-16, wherein the oligonucleotide comprises a modified internucleoside linkage. 18. The composition of claim 17, wherein the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. 19. The composition of claim 18, wherein the modified internucleoside linkage comprises one or more phosphorothioate linkages. 20. The composition of any one of claims 1-19, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. 21. The composition of any one of claims 1-20, wherein the oligonucleotide comprises a modified nucleoside. 22. The composition of claim 21, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’,4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2'-O-alkyl, 2’-C-allyl, 2’-O-allyl, 2'-fluoro, or 2'-deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. 23. The composition of claim 22, wherein the modified nucleoside comprises a LNA. 24. The composition of claim 22, wherein the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. 25. The composition of claim 22, wherein the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. 26. The composition of claim 22, wherein the modified nucleoside comprises a 2' O-alkyl modified nucleoside. 27. The composition of any one of claims 1-26, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. - 318 - Attorney Docket No.54462-772.601 28. The composition of any one of claims 1-27, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. 29. The composition of claim 28, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, α-tocopherol, stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof. 30. The composition of claim 28, wherein the lipid comprises a lipid moiety comprising ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. 31. The composition of claim 30, wherein the lipid moiety comprises ETL20. 32. The composition of any one of claims 1-27, wherein the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. 33. The composition of claim 32, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. 34. The composition of any one of claims 1-27, wherein the oligonucleotide comprises an integrin or integrin targeting ligand attached at a 3’ or 5’ terminus of the oligonucleotide. 35. The composition of claim 34, wherein the integrin comprises integrin alpha-v-beta-6 or integrin alpha-v-beta-3 (αvβ3) or a combination thereof. 36. The composition of claim 34, wherein the integrin targeting ligand comprises an arginine- glycine-aspartic acid (RGD) peptide. 37. The composition of any one of claims 1-36, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. 38. The composition of claim 37, wherein the sense strand is 12-30 nucleosides in length. 39. The composition of claim 37, wherein the antisense strand is 12-30 nucleosides in length. 40. The composition of claim 1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). 41. The composition of claim 40, wherein the ASO is 12-30 nucleosides in length. 42. The composition of any of the claims 1-41, wherein the composition is administered by an intra-articular administration. 43. A method of treating a subject having an arthropathy, comprising administering an effective amount of the composition of any one of claims 1-42 to the subject. 44. The method of claim 43, wherein the method comprises an intra-articular administration of the effective amount of the composition. 45. The method of claim 44, wherein the intra-articular administration is ultrasound-guided. 46. A composition comprising an oligonucleotide that inhibits the expression of PLOD2, wherein the oligonucleotide comprises: (a) an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; - 319 - Attorney Docket No.54462-772.601 (b) an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1. 47. The composition of claim 46, wherein the sense sequence comprises a modification pattern selected from the group consisting of 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. 48. The composition of claim 46, wherein the antisense sequence comprises a modification pattern selected from the group consisting of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. 49. The composition of claim 46, wherein any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O- methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O- methyl modified purines. 50. The composition of claim 46, wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; - 320 - Attorney Docket No.54462-772.601 all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’- fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’- fluoro modified purines. 51. The composition of claim 46, wherein any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’- O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’- O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside. 52. The composition of claims 1 or 46, further comprising a pharmaceutically acceptable carrier. - 321 - Attorney Docket No.54462-772.601 53. The composition of any of the claims 46-52, wherein the composition is administered by an intra-articular administration. 54. A method of treating a subject having an arthropathy, comprising administering an effective amount of the composition of any one of claims 46-53 to the subject. 55. The method of claim 54, wherein the arthropathy comprises osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the ankle, osteoarthritis of the spine, osteoarthritis of the hands or feet, temporomandibular joint (TMJ) disorders, polyosteoarthritis, post-traumatic osteoarthritis, arthrosis, arthralgia, degenerative joint disease, or a combination thereof. 56. The method of claim 54, wherein the method comprises an intra-articular administration of the effective amount of the composition. 57. The method of claim 56, wherein the intra-articular administration is ultrasound-guided. 58. A composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a sequence of Table 3. 59. A composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. 60. A composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 1; and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. - 322 - Attorney Docket No.54462-772.601 61. A composition comprising an oligonucleotide that modulates the expression of PLOD2, wherein the oligonucleotide comprises an siRNA comprising an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 1; wherein the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, 155S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. - 323 -
PCT/US2025/029173 2024-05-15 2025-05-13 Treatment of plod2 related diseases and disorders Pending WO2025240499A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463648147P 2024-05-15 2024-05-15
US63/648,147 2024-05-15

Publications (1)

Publication Number Publication Date
WO2025240499A1 true WO2025240499A1 (en) 2025-11-20

Family

ID=97720673

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/029173 Pending WO2025240499A1 (en) 2024-05-15 2025-05-13 Treatment of plod2 related diseases and disorders

Country Status (1)

Country Link
WO (1) WO2025240499A1 (en)

Similar Documents

Publication Publication Date Title
EP4352231A1 (en) Treatment of angptl4 related diseases
US20250195555A1 (en) Treatment of hgfac related diseases and disorders
KR20240163743A (en) Modified oligonucleotides
US20240287518A1 (en) Treatment of mtres1 related diseases and disorders
US20250313841A1 (en) Treatment of mst1 related diseases and disorders
WO2025240499A1 (en) Treatment of plod2 related diseases and disorders
WO2025240482A1 (en) Treatment of cspg4 related diseases and disorders
WO2025240505A1 (en) Treatment of colgalt2 related diseases and disorders
WO2023230478A2 (en) Treatment of sos2 related diseases and disorders
WO2023250327A1 (en) Treatment of gpam related diseases and disorders
EP4355355A1 (en) Treatment of plin1 related diseases and disorders
WO2023107896A1 (en) Treatment of fgg related diseases and disorders
KR20240033228A (en) Treatment of MST1-related diseases and disorders
WO2025137323A1 (en) Treatment of cpn1 related diseases and disorders
EP4540391A2 (en) Treatment of ms4a4e related diseases and disorders
WO2025059328A1 (en) Modified oligonucleotides
WO2025111565A1 (en) Treatment of sos2 related diseases and disorders
WO2025222056A1 (en) Treatment of cdhr3 related diseases and disorders
WO2025137167A2 (en) Treatment of gpam related diseases and disorders
US20240287519A1 (en) Treatment of dkk2 related diseases and disorders
WO2024118979A1 (en) Treatment of mtres1 related diseases and disorders
WO2025059326A1 (en) Modified oligonucleotides
WO2024206673A2 (en) Treatment of fgg related hearing disorders
WO2024137663A2 (en) Treatment of dkk2 related diseases and disorders
WO2025158407A2 (en) Treatment of mtres1 related diseases and disorders