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WO2025137323A1 - Traitement de maladies et de troubles liés à cpn1 - Google Patents

Traitement de maladies et de troubles liés à cpn1 Download PDF

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Publication number
WO2025137323A1
WO2025137323A1 PCT/US2024/061088 US2024061088W WO2025137323A1 WO 2025137323 A1 WO2025137323 A1 WO 2025137323A1 US 2024061088 W US2024061088 W US 2024061088W WO 2025137323 A1 WO2025137323 A1 WO 2025137323A1
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Prior art keywords
oligonucleotide
sense strand
composition
modified
measurement
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English (en)
Inventor
Omri GOTTESMAN
Shannon BRUSE
Paul BUSKE
Brian CAJES
David Lewis
Madeline LUTH
Gregory Mcinnes
Jason O'rourke
David Rozema
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Empirico Inc
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Empirico Inc
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Publication of WO2025137323A1 publication Critical patent/WO2025137323A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • 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
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • 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

Definitions

  • CPN1 disorders are becoming increasingly abundant, and may affect a wide variety of people.
  • the fracture risk measurement is decreased by about 10% or more, as compared to prior to administration.
  • compositions comprising an oligonucleotide that targets carboxypeptidase N subunit 1 (CPN1) and when administered to a subject in an effective amount improves a height measurement.
  • the height measurement comprises a change in a standing height measurement or a change in a sitting height measurement.
  • the height measurement is improved by about 10% or more, as compared to prior to administration.
  • compositions comprising an oligonucleotide that targets carboxypeptidase N subunit 1 (CPN1) and when administered to a subject in an effective amount improves a bone measurement.
  • the radiographic measurement comprises radiographic fracture healing and fracture union measurement, or a time to radiographic fracture healing and fracture union measurement. In some embodiments, the radiographic measurement is improved by about 10% or more, as compared to prior to administration.
  • compositions comprising an oligonucleotide that targets carboxypeptidase N subunit 1 (CPN1) and when administered to a subject in an effective amount decreases a creatine kinase measurement.
  • the creatine kinase measurement comprises a blood creatine kinase measurement. In some embodiments, the creatine kinase measurement is decreased by about 10% or more, as compared to prior to administration.
  • 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 or ETL28.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (av06) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide.
  • thymine (T) may be replaced with uracil (U).
  • the antisense strand may comprise an angiopep-2.
  • the antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand.
  • LRP lipoprotein receptor related protein
  • the antisense strand may comprise a glucose transporter protein.
  • the antisense strand may comprise a LDL receptor ligand.
  • 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.
  • 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 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.
  • 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 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 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 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
  • 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.
  • 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 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.
  • 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
  • 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. [0046] 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subsets A, B, C, D, E, F, G, H and I, respectively, 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 subsets A, B, C, D, E, F, G, H and I, respectively.
  • any of the aforementioned siRNAs may include an antisense strand of an antisense strand sequence of Tables 6-10, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.
  • 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 1 (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 a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of Tables 6-10, comprising at least 15, 16, 17, 18, 19, or 20 contiguous nucleotides of a sequence of Tables 6-10.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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. 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.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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 CPN1 mRNA sequence such as SEQ ID NO: 3837; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • 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, ormore contiguous nucleosides of one of SEQ ID NO: 3837.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified intemucleoside linkage.
  • the oligonucleotide comprises a modified intemucleoside linkage.
  • the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified intemucleoside 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 intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased 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 CPN1, wherein the oligonucleotide comprises the modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2’-C-allyl, 2'-fluoro, or 2 -deoxy, or a combination thereof.
  • the modified nucleoside comprises a LNA.
  • 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'-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises a 2’-O-methoxyethyl group (“MOE”). In some embodiments, the modified nucleoside comprises a 2'-C-alkyl group. In some embodiments, the modified nucleoside compnses a methoxyethyl.
  • position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O-methoxyethyl thymine.
  • the modified nucleoside comprises 2'-O-methyl.
  • the modified nucleoside comprises a 2'-O-allyl group.
  • the modified nucleoside comprises a 2'-fluoro group.
  • the modified nucleoside comprises a 2'-deoxy group.
  • the modified nucleoside comprises a 2'-O-methyl nucleoside, 2’-deoxyfluoro nucleoside, 2 , -O-N-methylacetamido (2’-0-NMA) nucleoside, a 2’-O- dimethylaminoethoxyethyl (2 -0-DMAE0E) nucleoside, 2'-O-aminopropyl (2 -O-AP) nucleoside, or 2'- ara-F, or a combination thereof.
  • the modified nucleoside comprises a 2'-O-methyl nucleoside.
  • the modified nucleoside comprises a 2'-deoxyfluoro nucleoside.
  • the modified nucleoside comprises a 2 -0-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-DMAE0E 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 acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.
  • the modified nucleoside comprises a glycol nucleic acid (GNA).
  • GNA glycol nucleic acid
  • the modified nucleoside comprises an unlocked nucleic acid.
  • An unlocked nucleic acid may comprise the following structure: 3’ nucleotide 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 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 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 composition comprises an oligonucleotide that inhibits the expression of CPN1, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof.
  • the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5 ’ end of the sense strand.
  • the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand.
  • 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 comprise 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 punnes include adenine (A), inosine (I), 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.
  • all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2 ’-fluoro and 2 -0- 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 -0- 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. 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’ -fluoromodified nucleoside.
  • 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.
  • at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside.
  • 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 nucleoside
  • 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 punne 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.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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 CPN1, 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 a-tocopherol, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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 since they may target or bind a mannose receptor such as CD206.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or tri valent 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 oligonucleotide may include purines.
  • purines include adenine (A), inosine (I), 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 purmes. 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. 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.
  • 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 -0- 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 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.
  • 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’-0-methyl modified purines.
  • all pynmidines 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 2’0Me 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 2’0Me 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 punnes are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • 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.
  • 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 (av(36) bay be an example of an epithelial-specific integrin av[36 may be a receptor for an ECM protein or TGF-beta latency-associated peptide (LAP).
  • Integrin av[36 may be expressed in a cell or tissue. Integrin av[36 may be expressed or upregulated in injured pulmonary epithelium.
  • the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin av[36.
  • An integrin targeting ligand may include a compound that has affinity for integrin av[36 or integrin alpha-v-beta-3 (av 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 avP3 or uvP6).
  • 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.
  • an oligonucleotide that targets CPN 1 further comprises a targeting ligand that targets a receptor which mediates delivery to a specific CNS tissue.
  • the targeting ligand is conjugated to the oligonucleotide.
  • the targeting ligand is selected from the group consisting of 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.
  • the targeting ligand is selected from the group consisting of trans-retinol, RGD peptide, LDL receptor ligand, and carbohydrate-based ligands.
  • the targeting ligand is a RGD peptide, such as H-Gly-Arg-Gly-Asp-Ser-Pro-Lys-Cys-OH or Cyclo(-Arg-Gly- Asp-D-Phe-Cys).
  • 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 CPN1, 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.
  • 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.
  • 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. For example, the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide.
  • 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- 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, 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. In some embodiments, there are not three 2’-fluoro-modified purines in a row.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modified 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.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modified 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.
  • 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-modified 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 vmyl 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.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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 CPN1, 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 a-tocopherol, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, wherein the oligonucleotide comprises a hydrophobic ligand or moiety.
  • the hydrophobic ligand or moiety comprises cholesterol.
  • the hydrophobic ligand or moiety comprises a cholesterol derivative
  • the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide.
  • the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide.
  • 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). 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.
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.
  • the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl.
  • the lipid comprises cholesterol.
  • the lipid includes a sterol such as cholesterol.
  • the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl.
  • the lipid comprises phenyl para C12. The lipid moiety may be esterified.
  • the oligonucleotide comprises any aspect of the following structure:
  • the oligonucleotide comprises any aspect some embodiments, the oligonucleotide comprises any aspect of the following structure: some embodiments, the oligonucleotide comprises any aspect of the following structure: 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.
  • 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.
  • the lipid moiety comprises an alcohol or ether. [00101] 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.
  • 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 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.
  • 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. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.
  • 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 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: . some embodiments, n is 1 -3. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 3.
  • 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.
  • 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. 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.
  • the lipid may be attached to the oligonucleotide by a linker.
  • the linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, 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 CPN1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or tri valent 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 CPN1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.
  • the composition comprises GalNAc.
  • the composition comprises a GalNAc derivative.
  • the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide.
  • the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide.
  • 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 CPN1, wherein the oligonucleotide comprises a GalNAc moiety.
  • the GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below.
  • described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II): or a salt thereof, wherein
  • Q is selected from:
  • C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -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 , -S(O)R 7 , and Ci. 6 alkyl, wherein the Ci- 6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH 2 ;
  • R 1 is a linker selected from: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-_ -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O- , -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -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)(
  • Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -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 ;
  • R 3 and R 4 are each independently selected from:
  • each R 5 is independently selected from:
  • each R 6 is independently selected from: hydrogen; halogen, -CN, -NO 2 , -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 ,
  • Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -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 ; each R 7 is independently selected from: hydrogen;
  • 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.
  • 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, -NO 2 , -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 C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 , and -NH 2 .
  • 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 .
  • 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)(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-.
  • R 1 is selected from - OP(O)(OR 7 )O- and -OP(OR 7 )O-.
  • R 2 is selected from C1.3 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 C1.3 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 Ci-g 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, -N0 2 , -NH 2 , and C1.3 alkyl;
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -0P(0)(0 )0-, -OP(S)(O )0-, -OP(O)(S )0-, and - OP(OR 7 )O-;
  • R 2 is Ci alkyl substituted with -OH or -OC(O)CH 3 ;
  • 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 intemucleoside linkages.
  • the one or more modified intemucleoside 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 intemucleoside linkages.
  • the compound binds to an asialoglycoprotein receptor.
  • the compound targets a hepatocyte.
  • 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.
  • 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. [00117] Some embodiments include the following, where J is the oligonucleotide: 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:
  • J The structure in this compound attached to the oligonucleotide (J) may be referred to as "ETL I 7,” 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:
  • Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:
  • Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:
  • 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:
  • J 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
  • 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.
  • 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.
  • J is the oligonucleotide: 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:
  • J 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.
  • 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.
  • described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):
  • Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker 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 , - S(O)R 7 , and Cue alkyl, wherein the Cue alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH 2 ;
  • R 1 is a linker selected from: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, - OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -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-, -SP(O)(O )O )
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J 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:
  • 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:
  • J 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.
  • J and K are independently H, a GalNAc moiety or oligonucleotides:
  • 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.
  • ademA GalNAc ademG GalNAc
  • ademC GalNAc ademC GalNAc
  • ademU GalNAc oligonucleotide
  • 2-4 GalNAc moieties are attached to the oligonucleotide.
  • 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.
  • sugar moieties comprising the following structure, where R is an oligonucleotide:
  • 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.
  • Rin some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J 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.
  • J is an oligonucleotide and X is S or 0: .
  • 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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 or K comprises an oligonucleotide:
  • 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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 Nu is an oligonucleotide:
  • Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • Nu in some instances comprises one or more phosphates linking to the oligonucleotide.
  • Nu in some instances comprises a phosphate linking to the oligonucleotide.
  • Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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 structures, where J is an oligonucleotide:
  • 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:
  • 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 J’ is an oligonucleotide or a GalNAc moiety:
  • J or J’ The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “GalNAc Gib,” and is an example of a GalNAc moiety.
  • J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphate linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety:
  • J or J’ The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “lgT3,” and is an example of a GalNAc moiety.
  • J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphate linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker:
  • J The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “5gn2c6,” 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.
  • X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or 0.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[Gal-6]s[Gal-6]s[Gal-6],” 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.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” 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.
  • [00161] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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.
  • the composition comprises an oligonucleotide that inhibits or reduces the expression of target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5’- NfsnNfhNfhNfNfhNfhNfhNfnNfhNfsnsn-3’.
  • the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfhnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 3S: 5’-nsnsnnNfhNfnNfhnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfhNfnNfNfnNfnNfnNfhNfnNfsnN- moiety-3’. In some embodiments, the sense strand comprises modification pattern 5S: 5’- nsnsnnNfhNfNfnnnnnnnnnsnN-moiety-3’. In some embodiments, the moiety in modification pattern 4 S or 5 S is a lipophilic moiety.
  • the moiety in modification pattern 4S or 5S is a lipid moiety.
  • the sense strand comprises modification pattern 6S: 5’- NfsnsNfhNfnNfiiNfhNfnNfhNfnNfiiNfsnsn-3 ’ .
  • the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfnnnnnnmmnsnsn-3’.
  • the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfiinnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern IOS: 5’- NfsnsnnNfiiNfnNfnNfiiNfiiNfnnsn-3’. In some embodiments, the sense strand comprises modification pattern 1 IS: 5’-nsnsNfhNfiiNfnNfiiNfnNfnnnNfiiNfsnsn-3’.
  • the sense strand comprises modification pattern 12S: 5’- NfsnsNfhNfnNfnNfimnNfnNfhNfsnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 13S: 5’- nsnsnnnnNfiiNfhNfiiNfnNfiiNfnNfsn-3’. In some embodiments, the sense strand comprises modification pattern 14S: 5’-snnnnnnNfNfNfNfnnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 15S: 5’-snnnnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 16S: 5’- snnnnNfnNfNfdNnnnnnnnnnsnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 17S: 5’-snnnnnNfNfnNfiinnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 18S: 5’-snnnnnnNfnNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 19S: 5’-snnnnNfiiNfiiNfiiNfnnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfiiNfiiNfnnnnnnnnnnnnnsn-3’.
  • the sense strand comprises modification pattern 21S: 5’-snnnnNfNfhnNfNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 22S: 5’- snnnnNfnnNfNfNfhnnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 23 S: 5’-snnrmnNfiiNfNfhnnnmmnnnsnsn-3’.
  • the sense strand comprises modification pattern 24S: 5’-snnnnnnnNfNfNfhnnnmmnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25S: 5’-snnnnnNfNfNfNfimnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNfNfNfNfnnnnnnnnnnsn- 3’.
  • the sense strand comprises modification pattern 27S: 5’- snnnnnnnNfNfiiNfimnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 28S: 5’-snnnnNfNfiiNfNfnNfimnnnnnnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’-snnnnnnnNfnNfhnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 30S: 5’-snnnnNfNfiinNfhNfnnnnnnnnsnsn-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’- snnnnnNfNfdNNfnnnnnnnnnsnsn-3 ’ .
  • the sense strand comprises modification pattern 33S: 5'-snnnnNfiiNfnNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34S: 5'-snnnnNfnNfNfdNNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S: 5'-snnnnnNfNfNfiiNfimnnnnsnsn-3'.
  • the sense strand comprises modification pattern 36S: 5'- snnnnnNfNfNfiiNfhnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnNfhNfNfdTNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S: 5'-snnnnNfnNfNfNfnnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 39S: 5'-snnnnNfiiNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40S: 5'-snnnnNfiiNfNfdNnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 41S: 5’-snnnnnnnNfNfnnnnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 42S: 5'- snnnnNfnNfNfdTnNfnnnnnnnsnsn-S'. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnnnNfiiNfiiNfhnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S: 5'-snnnnNfnNfNfNfNfimnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 45S: 5'-snnnnnNfimNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnnnNfNfNfNfimnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S: 5'-snnnnnNfNfnNfhNfnnnnnnnnsnsn- 3'.
  • the sense strand comprises modification pattern 48S: 5'- nnNfnNfiiNfiiNfiiNfnNfnnnNfiiNfsn-3'. In some embodiments, the sense strand comprises modification pattern 49S: 5'- NfnNfnNfiiNfNfNfhNfnNfnNfhNfiiNfsn-3'. In some embodiments, the sense strand comprises modification pattern 50S: 5'-nnnnNfNfNfNfNfiinnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 5 IS: 5'-nnnnNfNfNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 52S: 5'- snnnnmnNfNfNfNfiinnnnnmnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 53S: 5'-snnnnmnNfNfNfNfiinnnnmnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 54S: 5'-snnnnmnNfNfNfimnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S: 5'-snnnnmnNfNfNfhnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 56S: 5'- snnnnmNfNfNfNfiinnmnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 57S: 5'-snnnnnmNfNfNfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S: 5'-nnnnmnNfNfNfNfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S: 5'-snsnnnnNfNfNfNfimnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 60S: 5'- snnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61S: 5'-snnnnmNfhNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62S: 5'-snnnnmnNfNfNfNfnnnmnnnninsnsn-3'.
  • the sense strand comprises modification pattern 63S: 5'-snnnnmnNfNfNfNfrinnnmnninnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64S: 5'- nnnnmnnNfNfNfimnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S: S'-nsnsnnmnN ClSJNfNfNfimnnmnnnnnnsnsn-S'.
  • the sense strand comprises modification pattern 66S: 5'-nnnnnnnnNfNfhnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67S: 5'-nnnnNfnNfdNNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'-nnnnnnnNfNfiiNfimnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'- nnnnNfimNfiiNfhnnnnnnnsnsn-3'.
  • the sense strand comprises modification patem 70S: 5'-nnnnnNfiiNfNfiinnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 7 IS: 5'-nnnnnNfnNfNfhNfhnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 72S: S'-nnnnnnNfiiNfNfimnnnnnnnsn-S'. In some embodiments, the sense strand comprises modification pattern 73 S: 5'-nnnnNfiiNfnNfimnnnnnnnnsnsnsn-3.
  • the sense strand comprises modification pattern 74S: 5'-nnnnNfNfhnNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'- nnnnNfnnnNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'-nnnnNfNfimNfiiNfiinnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnNfiiNfhNfhmmnnnnsnsn-3'.
  • the sense strand comprises modification pattern 78S: 5'-nnnnnNfNfhNfnNfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 79S: 5'-nnnnnNfNfNfhnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 80S: 5'-nnnnnNfNfNfnNfimnnnnnsnsn- 3'
  • the sense strand comprises modification pattern 8 IS: 5'- nnnnNfnnNfNfnnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 82S: 5'-nnnnNfhnNfNfiiNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 83 S: 5'-nnnnNfnNfiiNfhNfiinnnnnnnnnsnsn-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'-nnnnNfNfnNfNfiiNfhnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 86S: 5'-nnnnnnnNfNfNfNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 87S: 5'- nnnnnnNfNfNfhnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'-nnnnnnNfNfNfNfhnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 89S: 5'-nnnnnNfimNfNfhnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'-nnnnnNfnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 9 IS: 5'-nnnrmNfNfiiNfNfhnnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 92S: 5'-nnnnNfnnnNfNfhnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 93S: 5'- nnnnNfnnNfNfNfNfnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 94S: 5'-nnnnNfiiNfhNfNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 95S: 5'-nnnnNfnNfNfNfimnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 96S: 5'-nnnnNfNfnnNfNfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 97S: 5'-nnnnnnNfNfimnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 98S: 5'-nnnnNfnNfNfdNnnnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 99S: 5'- nnnnnnnNfnNfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 100S: 5'-nnnnNfnNfNfdTnNfimnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 101S: 5'-nnnnNfnNfNfdNnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfhNfNfdTnnnnnnnnnnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'- snnnnNfhNfNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 104S: 5'-snnnnNfNfhnNfhnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: S'-snnnnNfnnNfNfnNfnnnnnnnnsn-S'. In some embodiments, the sense strand comprises modification pattern 106S: S'-snnnnNfhnNfNfiinnnnnnnnnnsnm-S'.
  • the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’- snNfnNfiiNfnNfNfnnnnnNfhNfNfiisnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 109S: 5’-snnnnnmNfNfNfNfiinnnnmnnnnnnsnsn-3’.
  • the sense strand comprises modification pattern 1 IOS: 5'-nnnnnNfNfnNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 11 IS: 5’-NfsnNfnNfiiNfhNfnNfnNfhNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 112S: 5’- NfnNfiiNfiiNfnNfiiNfiiNfiiNfnNfsn-3’.
  • the sense strand comprises modification pattern 113S: 5’-nnnnnnNfhNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 114S: 5’-snnnnmnNfNfNfNfiinmnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 115S: 5 ’ -nNfiiNfnNfiiNfNfiinnnnNfnNfNfnsnsn-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 CPN1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’- nsNfsnNfiiNfnNfiiNfimnNfiiNfnNfiisnsn-3’.
  • the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnnNfhNfnnnsnsn-3’.
  • the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnNfhNfimnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’- nsNfsnNfnNfnnnnnnnnNfiiNfimnsnsn-3 ’ . In some embodiments, the antisense strand comprises modification pattern 5 AS: 5’-nsNfsnnnnnnnnnnnnNfnNfimnsnsn-3’.
  • the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfimnnNfnNfimnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfnNfiiNfhNfnNfnNfiiNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 8 AS: 5’-nsNfsnnnnnnnnnnnnnnnnnnnsnsnsn-3’.
  • the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfnNfimnnnNfhNfiinnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnNfsnNfiiNfnNfiiNfiiNfhNfnNfiisnsn-3’. In some embodiments, the antisense strand comprises modification pattern HAS: 5'-nsNfsnnnNfnNfnNfrmnNfhNfnNfnsnsn-3'.
  • the antisense strand comprises modification pattern 12AS: S'-nsNfsnnnNfnNfiiNfiiNfiiNfnNfiiNfiisnsn-S’. In some embodiments, the antisense strand comprises modification pattern 13AS: 5'- nsNfsnnNfnNfnnNfnNfiiNfhNfiiNfnsn-3’. In some embodiments, the antisense strand comprises modification pattern MAS: 5'-nsNfsnnNfhNfnNfhnnnNfhNfnNfnsnsn-3’.
  • the antisense strand comprises modification pattern 15AS: 5'-nsNfsnNfnnNfhNfnnnnNfhNfiiNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS: 5'- nsNfsnnnNfhNfnnnNfnNfhNfnNfhsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'-nsNfsnNfhnNfnnNfhNfhNfnNfhNfnsnsn-3’.
  • the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnnNfhnNfhnnNfnNfiiNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'- nsNfsnnnnNfhnNfiiNfnNfhNfnNfhsn-3’. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'-nsNfsnnnnNfhNfhnNfhNfhNfnNfhsnsn-3’.
  • the antisense strand comprises modification pattern 2 IAS: 5'-nsNfsnnnnNfnNfnnnnNfnNfhNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS: 5'- nsNfsnNfnNfnNfhnnnnNfhNfnNfhsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 23AS: 5'- VPnsNfsnnnNfhNfhrmnnNfhNfhnnsnsn-3'.
  • the antisense strand comprises modification pattern 24AS: 5'- VPnsNfsnNfnNfiiNfiiNfnNfhNfhNfnsn- 3'.
  • the sense strand comprises modification pattern 25 AS: 5'- VPnsNfsnnnNfhNfhNfoNfhNfnNfhNfnsn-3'.
  • the sense strand comprises modification pattern 26AS: 5'- VPnsNfsnnNfhNfrmNfhNfnNfnNfhNfhsnsn-3'.
  • the sense strand comprises modification pattern 27AS: 5'- VPnsNfsnNfonNfhNfhnnnNfhNfnNfhsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'- nsNfsnnNfnNfnnNfhNfnNfhsnsn-3'. In some embodiments, the sense strand comprises modification pattern 29AS: 5'-nsNfsnnNfhNfrmNfhnnNfhNfnnnsnsn-3'.
  • the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfnNfhNfhNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 3 IAS: 5'- nsNfsnnNfnNfnnNfnNfhNfhnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32AS: 5'-nsNfsnnnNfNfnnNfhNfhNfnNfhnnsnsn-3'.
  • the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfnNfNfhNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'- nsNfsnnNfnNfNfhnnNfhNfhnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35AS: 5'-nsNfsnnnNfNfnnNfhnnNfhNfnnnsnsnsn-3'.
  • the sense strand comprises modification pattern 36AS: 5'-nsNfsnnnnNfNfhNfhnnNfhNfhnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37AS: 5'- nsNfsnnNfn[NUNA]nnNfhnnNfhNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38AS: 5'-nsNfsnnNf[NUNA]NfhnNfnnnNfnNfiinnsnsn-3'.
  • the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfnNfhnNfhnnNfhNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40AS: 5'- 5VPnsNfsnnNfhNfhnNfhNfhNfnNfhnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 41AS: 5'-nnnNfnNfnNfhNfnNfnNfnNfhNfnsnsn-3'.
  • the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfnNfhNfhnnNfhNfiinnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43AS: 5'- nsNfsnnnNfNfnnNfiiNfhNfhNfnsn-3'. In some embodiments, the antisense strand comprises modification pattern 44AS: S'-nsNfsnnnNfhnnNfhnnNfhNfhNfnsnsn-S'.
  • the antisense strand comprises modification pattern 45AS: 5'-nsNfsnnnNfNfhnNfhnnNfnNfhNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfhnNfhnnNfhNfhnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 47AS: 5'-nsNfsnnnnNfNfhNfhNfhNfnNfhNfnsnsn-3'.
  • the antisense strand comprises modification pattern 48AS: S'-nsNfsnnNfnNfNfhNfnNfhNfnNfhNfhsnsn-S'. In some embodiments, the antisense strand comprises modification pattern 49AS: 5'- nsNfsnnNfnNfNfhnnNfhNfhNfiiNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfhNfnNfhnNfhNfnNfhNfnsnsn-3'.
  • the antisense strand comprises modification pattern 5 IAS: 5'-nsNfsnNfnNfhNfhNfnNfnNfhNfnnsnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfnNf[UNA]NfnNfhNfnNfnNfhnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNfNfhNfiiNfhNfnNfnnnsnsn-3'.
  • the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNfNfhnnNfhNfhNfhnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55AS: 5'- nsNfsnnnn[UNA]NfhnnNfiiNfiiNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 56AS: 5’-nsnsnNfnNfhNfhNfhNfhNfnNfhNfnsnsn-3’.
  • the antisense strand comprises modification pattern 57AS: 5’-nsNfsnNfnnNfhnNfhNfhNfhnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’-nsNfsnnnNfhNfhNfhNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 59AS: 5’-nsNfsnNfhnNfnnnnNfhNfhNfnNfhsnsn-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-hexa
  • the composition comprises an oligonucleotide that inhibits the expression of CPN1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS.
  • the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42AS, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 5OAs, 5 IAS, 52AS, 53AS, 54AS 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42AS, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 11 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS.
  • the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15 AS.
  • the sense strand comprises pattern 21S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, HAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 23S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 25S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS.
  • the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15 AS.
  • the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 3 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, BAS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 33S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 35S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 37S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 38S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 39S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 40S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS.
  • the sense strand comprises pattern 41S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 42S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 43S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 44S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 45S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 46S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 47S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 48S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 49S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 50S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS.
  • the sense strand comprises pattern 5 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 52S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 53S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 54S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 55S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 56S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 57S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 58S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 59S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 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 IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 61S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 62S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, I 3AS.
  • the sense strand comprises pattern 63S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 64S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 65 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 66S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 67S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 68S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15 AS. 16AS, 17AS, 18AS, BAS.
  • the sense strand comprises pattern 69S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 70S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 71S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 72S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 73S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 74S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 75S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 76S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, HAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 77S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 78S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 79S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 80S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS.
  • the sense strand comprises pattern 8 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15 AS. 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 82S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS.
  • the sense strand comprises pattern 83S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15 AS.
  • the sense strand comprises pattern 84S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, SAS, 10AS, HAS, 12AS, 13AS, 14AS, MAS, 16AS, 17AS, 18AS, 19AS, 20AS, 2 IAS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 85S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. MAS, 15AS, 16AS, I 7AS.
  • the sense strand comprises pattern 86S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS. I5AS. 16AS, I 7AS. 18AS, I 9AS.
  • the sense strand comprises pattern 87S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, MAS.
  • the sense strand comprises pattern 88S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS.
  • the sense strand comprises pattern 89S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 90S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 91S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 92S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 93S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 94S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 95S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 96S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 97S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 98S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS.
  • the sense strand comprises pattern 99S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 100S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 10 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 102S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 103S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 104S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, BAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 105S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 106S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS. 14AS, BAS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 107S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15 AS. 16AS, 17AS, 18AS, BAS.
  • the sense strand comprises pattern 108S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 109S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, I 9AS.
  • the sense strand comprises pattern 1 IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, BAS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 11 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 112S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 113S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 114S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern 115S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 2AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the antisense strand comprises pattern 3AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 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,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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,
  • the antisense strand comprises pattern 5AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 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
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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,
  • the antisense strand comprises pattern 1 IAS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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,
  • the antisense strand comprises pattern 13AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 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,
  • the antisense strand comprises pattern MAS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21 S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 25AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 30AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 31AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 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, 5 IS, 52S, 53S,
  • the antisense strand comprises pattern 32AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 35AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 40AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 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,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 45AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the antisense strand comprises pattern 47AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the antisense strand comprises pattern 48AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the antisense strand comprises pattern 50AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 55AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 57AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 58AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,
  • the antisense strand comprises pattern 59AS.
  • the sense strand comprises any one of modification patters IS, 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, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 3OS, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S,
  • the sense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS.
  • the antisense strand comprises modification pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13 AS.
  • the antisense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS.
  • the antisense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,
  • the sense strand or the antisense strand comprises modification pattern ASO1.
  • 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-methyl modified pyrimidines. In some embodiments, 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. 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.
  • purines of the sense strand comprise 2’-O-methyl modified purines
  • pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines
  • 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
  • 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, 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.
  • 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 punnes 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. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2’-fhioro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fhioro 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.
  • 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.
  • 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’-0-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 pyrim
  • 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 (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (i
  • 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’-0-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-0-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; (ii)
  • 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 -0- 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 -0- 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
  • 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 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 CPN 1 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 CPN 1 mRNA or a target protein.
  • the sense strand has the same sequence as the CPN1 mRNA. In some embodiments, there are 1-2 phosphorothioates at the 3’ end. In some embodiments, there are 1 or no phosphorothioate s 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.
  • 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, then 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, then position 9 is the only position with a 2’F modification in the sense strand.
  • both of these pyrimidines are the only two positions with a 2’F modification in the sense strand.
  • 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.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • 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.
  • 2’F and 2’0Me 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.
  • 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, 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.
  • 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.
  • pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides.
  • purines at positions 1-8 include a mixture of2’-fluoro and 2’-O-methyl modified nucleosides, and pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides.
  • pyrimidines at positions 1-8 include a mixture of 2’-fhioro 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 CPN 1 and when administered to a cell decreases expression of CPN1, 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 intemucleoside 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 intemucleoside 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 intemucleoside 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 having a sequence in accordance with any of SEQ ID NOs: 3675-3728.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3675-3728, at least 80% identical to any one of SEQ ID NOs: 3675-3728, at least 85% identical to of any one of SEQ ID NOs: 3675-3728, at least 90% identical to any one of SEQ ID NOs: 3675-3728, or at least 95% identical to any one of SEQ ID NOs: 3675-3728.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3675-3728, 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: 3675-3728, 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: 1889-3728.
  • the sense 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 sense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences.
  • 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 an overhang.
  • the sense strand may comprise a modification pattern described herein, such as a different set of modifications or modification pattern than the aforementioned sequences.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 3783-3836.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3783-3836, at least 80% identical to any one of SEQ ID NOs: 3783-3836, at least 85% identical to of any one of SEQ ID NOs: 3783-3836, at least 90% identical to any one of SEQ ID NOs: 3783-3836, or at least 95% identical to any one of SEQ ID NOs: 3783-3836.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3783-3836, 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: 3783-3836, 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: 3783-3836.
  • the sense 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 sense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences.
  • 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 an overhang.
  • the sense strand may comprise a modification pattern described herein, such as a different set of modifications or modification pattern than the aforementioned sequences.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3729-3782.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3729-3782, at least 80% identical to any one of SEQ ID NOs: 3729-3782, at least 85% identical to of any one of SEQ ID NOs: 1838-3674, at least 90% identical to any one of SEQ ID NOs: 3729-3782, or at least 95% identical to any one of SEQ ID NOs: 3729-3782.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3729-3782, 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: 3729-3782, or an antisense strand sequence thereof having 1 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: 3729-3782.
  • 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 may include the first 19 nucleotides of any of the aforementioned sequences.
  • 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, such as a different set of modifications or modification pattern than the aforementioned sequences.
  • the antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 3838-3849 or 3909.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3838-3849 or 3909, at least 80% identical to any one of SEQ ID NOs: 3838-3849 or 3909, at least 85% identical to of any one of SEQ ID NOs: 3838-3849 or 3909, at least 90% identical to any one of SEQ ID NOs: 3838-3849 or 3909, or at least 95% identical to any one of SEQ ID NOs: 3838-3849 or 3909.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3838-3849 or 3909, 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: 3838-3849 or 3909, 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: 3838-3849 or 3909.
  • the sense 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 sense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences.
  • 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 an overhang.
  • the sense strand may comprise a modification pattern described herein, such as a different set of modifications or modification pattern than the aforementioned sequences.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3850-3860 or 3910-3919.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3850-3860 or 3910-3919, at least 80% identical to any one of SEQ ID NOs: 3850-3860 or 3910-3919, at least 85% identical to of any one of SEQ ID NOs: 3850- 3860 or 3910-3919, at least 90% identical to any one of SEQ ID NOs: 3850-3860 or 3910-3919, or at least 95% identical to any one of SEQ ID NOs: 3850-3860 or 3910-3919.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3850-3860 or 3910-3919, 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: 3850-3860 or 3910-3919, or an antisense strand sequence thereof having 1 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: 3850-3860 or 3910-3919.
  • 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 may include the first 19 nucleotides of any of the aforementioned sequences.
  • 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, such as a different set of modifications or modification pattern than the aforementioned sequences.
  • the antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • 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 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: 3675-3728, 3783-3836, 3838-3849 or 3909.
  • 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 a LDL receptor ligand.
  • LRP lipoprotein receptor related protein
  • 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, lgT3, 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 or ETL28.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • thymine (T) may be replaced with uracil (U).
  • 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: 3729-3782, 3850-3860 or 3910-3919.
  • the antisense stand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sinus GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 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 or ETL28.
  • the lipid moiety is ETL20.
  • Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (avP6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.
  • avP6 integrin alpha-v-beta-6
  • RGD arginine-glycine-aspartic acid
  • 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 Table 15.
  • 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 Table 15.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of Table 15, 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 Table 15, 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 Table 15.
  • the sense strand or 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 sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences.
  • the sense strand or 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 sense strand or antisense strand may comprise an overhang.
  • the sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than Table 15).
  • the sense strand or 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, and LDL receptor ligand.
  • 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 Table 15, comprising at least 15, 16, 17, 18, 19, or 20 contiguous nucleotides of a sequence of Table 15.
  • 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 Table 16.
  • 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 Table 16.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of Table 16, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the ASO comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 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,
  • 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.
  • the composition is formulated for administration.
  • the administration is systemic.
  • the administration is intravenous.
  • the administration is by injection.
  • the administration is systemic.
  • the administration is by parenteral administration.
  • the administration is local (e.g., to a particular organ or tissue).
  • the administration is by inhalation.
  • the administration is topical.
  • the administration is by infusion.
  • the administration is by injection.
  • the administration is intravenous (e.g., by intravenous injection or infusion).
  • the administration may be to joint tissue (e.g., by intraarticular injection). In some embodiments, the administration may be to airway or lung tissue (e.g., by intranasal, intratracheal or inhaled administration). In some embodiments, the administration may be to skin or connective tissue (e.g., by topical administration or injection to the skin).
  • Some embodiments relate to a method of improving a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of improving the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration improves the disorder in the subject. In some embodiments, the composition improves the disorder in the subject.
  • kits 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 intemucleoside 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 include instructions for use, such as methods for use in a method described herein.
  • composition described herein 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.
  • 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. The disorder may comprise a disease.
  • 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.
  • the composition prevents, inhibits, or reverses the disorder in the subject.
  • 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. [00205] 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.
  • 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 systemic. In some embodiments, the administration is by parenteral administration. In some embodiments, the administration is local (e.g., to a particular organ or tissue) In some embodiments, the administration is by inhalation. In some embodiments, the administration is topical. In some embodiments, the administration is by infusion. In some embodiments, the administration is by injection. In some embodiments, the administration is intravenous (e.g., by intravenous injection or infusion). In some embodiments, the administration is subcutaneous (e.g., by subcutaneous injection).
  • the administration is intraperitoneal. In some embodiments, the administration is intraparenchymal. In some embodiments, the administration is intramuscular (e.g., by intramuscular injection). In some embodiments, the administration may be to an eye tissue (e.g., by intravitreal, intracameral or subconjunctival injection, or by topical administration to the eye). In some embodiments, the administration may be to a central nervous system tissue (e.g., brain or spinal cord or spinal canal). In some embodiments, the administration is intracerebroventricular or intrathecal (e.g., by intrathecal injection or infusion). In some embodiments, the administration may be to joint tissue (e.g., by intraarticular injection).
  • the bone-related disease or disorder comprises osteopenia. In some embodiments, the bone-related disease or disorder comprises loss of bone mineral density and bone mass. In some embodiments, the bone-related disease or disorder comprises fractures. In some embodiments, the bone- related disease or disorder comprises Paget’s disease of bone (osteitis deformans). In some embodiments, the bone-related disease or disorder comprises hypercalcemia. In some embodiments, the bone -related disease or disorder comprises multiple myeloma and solid-tumor-related bone metastases.
  • the bone-related disease or disorder comprises decreased bone mass.
  • the decreased bone mass is in a man treated with androgen-deprivation therapy or a woman treated with aromatase inhibitor therapy.
  • the decreased bone mass is in a man treated with androgen-depnvation therapy.
  • the decreased bone mass is in a woman treated with aromatase inhibitor therapy.
  • the bone-related disease or disorder comprises a bone metastases.
  • the bone metastases comprise multiple myeloma-related bone metastases or solid tumor-related bone metastases.
  • the bone metastases comprise multiple myeloma- related bone metastases.
  • the bone metastases comprise solid tumor-related bone metastases.
  • the subject is male. In some embodiments, the subject is female.
  • the subject has a body mass index (BMI) of 15, 16, 17, 18, 19, 20, 21,
  • 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.
  • the baseline BMD measurement is a baseline BMD of the femoral neck. In some embodiments, the baseline BMD measurement is a baseline BMD of the femoral trochanter. In some embodiments, the baseline BMD measurement is a baseline BMD of the radius. In some embodiments, the baseline BMD measurement is obtained by an assay such as central dual energy x-ray absorptiometry, peripheral dual energy x-ray absorptiometry, quantitative computed tomography, or quantitative ultrasound.
  • the baseline measurement is a baseline fracture risk measurement.
  • the baseline fracture risk measurement is a baseline bone fracture risk measurement, a baseline risk of vertebral fractures measurement, a baseline risk of nonvertebral fractures measurement, a baseline risk of hip fracture measurement, or a baseline Fracture Risk Assessment (FRAX) score.
  • the baseline fracture risk measurement is a baseline bone fracture risk measurement.
  • the baseline fracture risk measurement is a baseline risk of vertebral fractures measurement.
  • the baseline fracture risk measurement is a baseline risk of nonvertebral fractures measurement.
  • the baseline fracture risk measurement is a baseline risk of hip fracture measurement.
  • the baseline fracture risk measurement is a baseline FRAX score.
  • the baseline fracture risk measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, central dual energy x-ray absorptiometry, peripheral dual energy x-ray absorptiometry, quantitative computed tomography or quantitative ultrasound.
  • the baseline fracture risk measurement is obtained by a questionnaire.
  • the baseline measurement is a baseline height measurement. In some embodiments, the baseline height measurement is a standing height measurement or a sitting height measurement. In some embodiments, the baseline height measurement is a standing height measurement. In some embodiments, the baseline height measurement is a sitting height measurement.
  • the baseline measurement is a baseline bone measurement
  • the baseline bone measurement is a baseline bone mineralizing surface index, a baseline bone formation index, a baseline bone resorption index, a baseline bone volume, a baseline bone trabecular and cortical thickness, a baseline bone histology marker, a baseline bone turnover marker, or a baseline bone histomorphometry marker.
  • the baseline bone measurement is a baseline bone mineralizing surface index.
  • the baseline bone measurement is a baseline bone formation index.
  • the baseline bone measurement is a baseline bone resorption index.
  • the baseline bone measurement is a baseline bone volume.
  • the baseline bone measurement is a baseline bone trabecular and cortical thickness. In some embodiments, the baseline bone measurement is a baseline bone histology marker. In some embodiments, the baseline bone measurement is a baseline bone turnover marker. In some embodiments, the baseline bone measurement is a baseline bone histomorphometry marker. In some embodiments, the baseline bone measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline creatine kinase measurement.
  • the baseline creatine kinase measurement is a baseline blood creatine kinase measurement.
  • the baseline creatine kinase measurement is a baseline tissue creatme kinase measurement.
  • the baseline creatine kinase measurement is obtained by an assay such as an enzymatic assay, an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline bone -related blood measurement.
  • the baseline bone-related blood measurement is a baseline blood calcium measurement, a baseline blood phosphate measurement, a baseline blood alkaline phosphatase measurement, a baseline blood parathyroid hormone measurement, a baseline blood osteocalcin measurement, a baseline blood 25-hydroxyvitamin D measurement, a baseline blood stromal cell -derived factor 1 measurement, or a baseline blood tartrate-resistant acid phosphatase measurement.
  • the baseline bone-related blood measurement is a baseline blood calcium measurement.
  • the baseline bone-related blood measurement is a baseline blood phosphate measurement.
  • the baseline bone-related blood measurement is a baseline blood alkaline phosphatase measurement.
  • the baseline bone-related blood measurement is a baseline blood parathyroid hormone measurement. In some embodiments, the baseline bone -related blood measurement is a baseline blood osteocalcin measurement. In some embodiments, the baseline bone-related blood measurement is a baseline blood 25-hydroxyvitamin D measurement. In some embodiments, the baseline bone-related blood measurement is a baseline blood stromal cell -derived factor- 1 measurement. In some embodiments, the baseline bone-related blood measurement is a baseline blood tartrate -resistant acid phosphatase measurement. In some embodiments, the baseline bone-related blood measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline height measurement. In some embodiments, the baseline height measurement is a baseline standing height measurement or a baseline sitting height measurement. In some embodiments, the baseline height measurement is a baseline standing height measurement. In some embodiments, the baseline height measurement is a sitting height measurement.
  • the baseline measurement is a baseline CPN 1 protein measurement.
  • the baseline CPN 1 protein measurement comprises a baseline CPN 1 protein level.
  • the baseline CPN 1 protein level is indicated as a mass or percentage of CPN 1 protein per sample weight.
  • the baseline CPN1 protein level is indicated as a mass or percentage of CPN1 protein per sample volume.
  • the baseline CPN1 protein level is indicated as a mass or percentage of CPN1 protein per total protein within the sample.
  • the baseline CPN 1 protein measurement is a baseline circulating CPN 1 protein measurement.
  • the baseline CPN 1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline CPN 1 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample.
  • the baseline CPN 1 mRNA measurement is a baseline circulating CPN 1 mRNA measurement.
  • the baseline CPN 1 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay.
  • the PCR comprises quantitative PCR (qPCR).
  • the PCR comprises reverse transcription of the CPN 1 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. In some embodiments, the sample is 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 blood is fractionated or centrifuged. 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. [00236] In some embodiments, the sample comprises a tissue.
  • the sample is a tissue sample.
  • the tissue comprises kidney, adipose, liver, brain, bone, or vascular tissue.
  • the baseline CPN1 mRNA measurement, or the baseline CPN1 protein measurement may be obtained in a kidney, adipose, liver, brain, or vascular sample obtained from the patient.
  • the tissue comprises liver tissue. The liver may include hepatocytes.
  • the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a hepatocyte. In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises an osteocyte. In some embodiments, the cell comprises an osteoblast. In some embodiments, the cell comprises an osteoclast.
  • the composition or administration of the composition affects a measurement such as a bone mineral density measurement, a fracture risk measurement, a height measurement, a bone measurement, a radiographic measurement, a creatine kinase measurement, a bone- related blood measurement, a CPN 1 protein measurement, or a CPN1 mRNA measurement, relative to the baseline measurement.
  • a measurement such as a bone mineral density measurement, a fracture risk measurement, a height measurement, a bone measurement, a radiographic measurement, a creatine kinase measurement, a bone- related blood measurement, a CPN 1 protein measurement, or a CPN1 mRNA measurement, relative to the baseline measurement.
  • 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 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.
  • additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample. [00241] 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.
  • 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 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.
  • the composition reduces the measurement relative to the baseline measurement.
  • an adverse phenotype of a bone disease or disorder may be 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.
  • the reduction is measured directly in the subject after administering the composition to the subject.
  • the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the measurement is decreased by about 10% or more, relative to the baseline measurement.
  • the measurement 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, relative to the baseline measurement. In some embodiments, the measurement is decreased 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 decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement 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%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased 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 composition increases or improves the measurement relative to the baseline measurement.
  • a protective bone disorder or disease phenotype may be 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.
  • the increase is measured directly in the subject after administering the composition to the subject.
  • 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.
  • the measurement is increased by about 10% or more, relative to the baseline measurement.
  • 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.
  • the measurement is increased 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 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.

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Abstract

L'invention concerne des compositions comprenant un oligonucléotide qui cible CPN1. L'oligonucléotide peut comprendre un petit ARN interférent (ARNsi) ou un oligonucléotide antisens (ASO). L'invention concerne également des méthodes de traitement d'états associés à des mutations du gène CPN1 qui comprennent la fourniture d'un oligonucléotide qui cible CPN1 chez un sujet.
PCT/US2024/061088 2023-12-22 2024-12-19 Traitement de maladies et de troubles liés à cpn1 Pending WO2025137323A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030167499A1 (en) * 2001-09-24 2003-09-04 Wisotzkey Robert G. Carboxypeptidase N (CPN) disruptions, compositions and methods relating thereto
WO2004094636A1 (fr) * 2003-04-24 2004-11-04 Galapagos Genomics N.V. Constructions demontables effectives d'arnsi
KR20140074559A (ko) * 2012-12-10 2014-06-18 (주)차바이오메드 심혈관질환 진단키트
US20180127747A1 (en) * 2007-12-18 2018-05-10 Dong Ki Lee Sirna structure for minimizing off-target effects and relaxing saturation of rnai machinery and the use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030167499A1 (en) * 2001-09-24 2003-09-04 Wisotzkey Robert G. Carboxypeptidase N (CPN) disruptions, compositions and methods relating thereto
WO2004094636A1 (fr) * 2003-04-24 2004-11-04 Galapagos Genomics N.V. Constructions demontables effectives d'arnsi
US20180127747A1 (en) * 2007-12-18 2018-05-10 Dong Ki Lee Sirna structure for minimizing off-target effects and relaxing saturation of rnai machinery and the use thereof
KR20140074559A (ko) * 2012-12-10 2014-06-18 (주)차바이오메드 심혈관질환 진단키트

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