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WO2025111565A1 - Traitement de maladies et de troubles associés à sos2 - Google Patents

Traitement de maladies et de troubles associés à sos2 Download PDF

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Publication number
WO2025111565A1
WO2025111565A1 PCT/US2024/057128 US2024057128W WO2025111565A1 WO 2025111565 A1 WO2025111565 A1 WO 2025111565A1 US 2024057128 W US2024057128 W US 2024057128W WO 2025111565 A1 WO2025111565 A1 WO 2025111565A1
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oligonucleotide
sense strand
antisense strand
sequence
modified
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Omri GOTTESMAN
Shannon BRUSE
Paul BUSKE
Brian CAJES
David Lewis
David JAKUBOSKY
Gregory Mcinnes
David Rozema
John VEKICH
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Empirico Inc
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Empirico Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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

  • Indications such as chronic kidney disease, diabetic nephropathy, gout, hyperuricemia, hypertension, cerebrovascular disease, type 2 diabetes, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, glaucoma, ocular hypertension, retinal diseases, age-related macular degeneration, choroidal neovascularization, geographic atrophy, diabetic retinopathy, non-alcoholic fatty liver disease, fibrotic liver disease, liver fibrosis, cirrhosis, or hairloss may affect a wide variety of persons. Improved therapeutics are needed.
  • composition comprising an siRNA that targets S0S2 and when administered to a subject in an effective amount increases an estimated glomerular filtration rate, or decreases a creatinine, blood urea nitrogen, proteinuria microalbuminuria measurement, or urine albumin creatinine ratio, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.
  • the estimated glomerular filtration rate is increased, or the creatinine, blood urea nitrogen, proteinuria, microalbuminuria measurement or urine albumin creatinine ratio is decreased, by about 10% or more, as compared to prior to administration.
  • composition comprising an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a blood urate measurement, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.
  • the blood urate measurement is decreased by about 10% or more, as compared to prior to administration.
  • composition comprising an siRNA that targets S0S2 and when administered to a subject in an effective amount decreases a systolic blood pressure measurement, a diastolic blood pressure measurement, a mean arterial pressure, or a pulse pressure, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.
  • the systolic blood pressure measurement, diastolic blood pressure measurement, mean arterial pressure, or pulse pressure is decreased by about 10% or more, as compared to prior to administration.
  • a composition comprising an siRNA that targets S0S2 and when administered to a subject in an effective amount decreases an intraocular pressure measurement, cup-disc ratio, optic nerve cupping, RPE pigmentation and reflectivity, drusen, Macular hemorrhage, choroidal neovascularization, edema, microaneurysms, intraretinal hemorrhage, macular ischemia, neovascularization, vitreous hemorrhage, or traction retinal detachment or increases a RNFL thickness or retinal thickness, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense
  • the intraocular pressure measurement , cup-disc ratio, optic nerve cupping, RPE pigmentation and reflectivity, drusen, Macular hemorrhage, choroidal neovascularization, edema, microaneurysms, intraretinal hemorrhage, macular ischemia, neovascularization, vitreous hemorrhage, or traction retinal detachment is decreased or the RNFL thickness or retinal thickness is increased by about 10% or more, as compared to prior to administration.
  • composition comprising an siRNA that targets S0S2 and when administered to a subject in an effective amount decreases a body mass index (BMI) measurement, a body weight measurement, a waist circumference measurement, a hip circumference measurement, a waist-hip ratio (WHR), a body fat percentage measurement, a hemoglobin A1C measurement, a blood glucose measurement, a glucose tolerance measurement, an insulin sensitivity measurement, a blood triglyceride measurement, or a non-HDL cholesterol measurement, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.
  • BMI body mass index
  • WHR waist-hip ratio
  • a body fat percentage measurement a hemoglobin A1C measurement
  • the siRNA comprises a sense strand and an antisense strand
  • the sense strand
  • the body mass index (BMI) measurement, the body weight measurement, the waist circumference measurement, the hip circumference measurement, the waist-hip ratio (WHR), the body fat percentage measurement, the hemoglobin A1C measurement, the blood glucose measurement, the glucose tolerance measurement, the insulin sensitivity measurement, the blood triglyceride measurement, or the non-HDL cholesterol measurement is decreased by about 10% or more, as compared to prior to administration.
  • composition comprising an siRNA that targets S0S2 and when administered to a subject in an effective amount decreases an alanine aminotransferase, aspartate aminotransferase, liver fat percentage measurement, liver fibrosis score, NAFLD activity score, or blood gamma-glutamyl transferase measurement, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence selected from any one of SEQ ID NOS: 11414-11443, or the antisense strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.
  • the alanine aminotransferase, aspartate aminotransferase, liver fat percentage measurement, liver fibrosis score, NAFLD activity score, or blood gamma-glutamyl transferase measurement is decreased by about 10% or more, as compared to prior to administration.
  • composition comprising an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence selected from any one of SEQ ID NOS: 11414-11468.
  • composition comprising an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, wherein the sense strand comprises a nucleoside sequence selected from any one of SEQ ID NOS: 1-5490, 11274-11303, or 11354-11383, wherein the sense sequence comprises a modification pattern selected from the group consisting of 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S .
  • composition comprising an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, wherein the antisense strand comprises a nucleoside sequence selected from any one of SEQ ID NOS: 5491-10980, 11304-11333, or 11384-11413, wherein the antisense sequence comprises a modification pattern selected from the group consisting of 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, or 16AS .
  • 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 lipid comprises a 5’ hydrophobic moiety comprising any one of the following structures: dotted line indicates a covalent connection to the end of the 5 ’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons.
  • the lipid comprises some embodiments, the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand, an arginine-glycine-aspartic acid (RGD) peptide, or a cholesterol ligand.
  • the oligonucleotide comprises a GalNAc ligand.
  • the GalNAc ligand comprises the structure:
  • J is the oligonucleotide.
  • a Genome Wide Association Study may detect associations between genetic variants and traits in a population sample.
  • a GWAS may enable better understanding of the biology of disease, and provide applicable treatments.
  • a GWAS can utilize genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome.
  • the most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease.
  • Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size.
  • OR odds ratios
  • beta beta coefficients
  • An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles.
  • SOS Ras/Rho guanine nucleotide exchange factor 2 encodes son of sevenless homolog 2 (also “S0S2”), a regulatory protein that may be involved in the positive regulation of ras proteins.
  • S0S2 may map to 14q21 within the human genome.
  • S0S2 may activate RAC1. Mutations in S0S2 may relate to Noonan syndrome. Here it is shown that loss-of-function S0S2 variants resulted in protective associations. Therefore, inhibition of S0S2 may serve as a therapeutic for treatment of SOS2-related diseases and disorders.
  • loss-of-function genetic variants of S0S2 may be protective for chronic kidney disease, diabetic nephropathy, gout, hyperuricemia, hypertension, cerebrovascular disease, type 2 diabetes, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, glaucoma, ocular hypertension, retinal diseases, age-related macular degeneration, choroidal neovascularization, geographic atrophy, diabetic retinopathy, non-alcoholic fatty liver disease, fibrotic liver disease, liver fibrosis, cirrhosis, or hair loss (e.g., androgenetic alopecia). Therefore, inhibition of S0S2 may serve as a therapeutic for treatment of these indications.
  • compositions comprising an oligonucleotide that targets S0S2.
  • the oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).
  • siRNA small interfering RNA
  • ASO antisense oligonucleotide
  • oligonucleotide that targets S0S2 to a subject in need thereof.
  • compositions comprising an oligonucleotide.
  • the composition comprises an oligonucleotide that targets SOS Ras/Rho guanine nucleotide exchange factor 2 (S0S2).
  • the composition consists of an oligonucleotide that targets S0S2.
  • the oligonucleotide reduces S0S2 mRNA expression in the subject.
  • the oligonucleotide reduces son of sevenless homolog 2 (S0S2) protein expression in the subject.
  • the oligonucleotide may include a small interfering RNA (siRNA) described herein.
  • the oligonucleotide may include an antisense oligonucleotide (ASO) described herein.
  • ASO antisense oligonucleotide
  • a composition described herein is used in a method of treating a disorder in a subject in need thereof.
  • Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein.
  • Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein.
  • Some embodiments include a composition comprising an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases S0S2 mRNA or S0S2 protein levels in a cell, fluid or tissue.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases S0S2 mRNA levels in a cell or tissue.
  • the cell is a liver cell (e.g., hepatocyte), kidney cell (e.g., podocyte), eye cell, or adipocyte.
  • the tissue is liver, kidney, eye, or adipose tissue.
  • the S0S2 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the S0S2 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the S0S2 mRNA levels are 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, about 95% or more, or about 100%, as compared to prior to administration.
  • the S0S2 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the S0S2 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the S0S2 mRNA levels are 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%, as compared to prior to administration.
  • the S0S2 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases S0S2 protein levels in a cell or tissue.
  • the cell is a liver cell (e.g., hepatocyte), kidney cell (e.g., podocyte), eye cell, or adipocyte.
  • the tissue is liver, kidney, eye, or adipose tissue.
  • the S0S2 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the SOS2 protein levels are decreased by about 10% or more, as compared to prior to administration.
  • the S0S2 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the S0S2 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the S0S2 protein levels are decreased by no more than about 10%, as compared to prior to administration.
  • the S0S2 protein levels are 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%, about 95% or more, or no more than about 100%, as compared to prior to administration. In some embodiments, the S0S2 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a kidney disease-related parameter.
  • the kidney disease comprises chronic kidney disease (CKD).
  • the kidney disease comprises diabetic nephropathy.
  • the kidney disease-related parameter may include a blood creatinine measurement.
  • the kidney disease-related parameter may include a blood urea nitrogen (BUN) measurement.
  • BUN blood urea nitrogen
  • the kidney disease- related parameter may include a BUN/ creatinine measurement.
  • the parameter may include a proteinuria measurement.
  • the parameter may include a microalbuminuria measurement.
  • the parameter may comprise a urine albumin creatinine ratio.
  • the kidney disease-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the kidney disease-related parameter 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, or about 90% or more, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the kidney disease- related parameter is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the kidney disease-related parameter 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 95%, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount increases a kidney disease-related parameter.
  • the kidney disease-related parameter may include a glomerular filtration rate (GFR).
  • the kidney disease- related parameter may include an estimated glomerular filtration rate (eGFR).
  • the kidney disease-related parameter is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the kidney disease-related parameter is increased by about 10% or more, as compared to prior to administration.
  • the kidney disease-related parameter 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, or about 100% or more, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the kidney disease-related parameter is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the kidney disease-related parameter 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%, as compared to prior to administration. In some embodiments, the kidney disease-related parameter is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration.
  • the kidney disease-related parameter is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a gout-related or hyperuricemia-related parameter.
  • the gout-related or hyperuricemia-related parameter may comprise a gout-related parameter.
  • the gout-related or hyperuricemia-related parameter may comprise a hyperuricemia-related parameter.
  • the gout-related or hyperuricemia-related parameter may include a blood urate measurement.
  • the gout-related or hyperuricemia-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the gout-related or hyperuricemia-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the gout-related or hyperuricemia-related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the gout-related or hyperuricemia-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the gout-related or hyperuricemia-related parameter is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the gout-related or hyperuricemia-related parameter 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 95%, as compared to prior to administration.
  • the gout-related or hyperuricemia- related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a cerebrovascular disease-related parameter.
  • the cerebrovascular disease-related parameter may include a hypertension-related parameter.
  • the hypertension-related parameter may include a systolic blood pressure measurement.
  • the hypertension-related parameter may include a diastolic blood pressure measurement.
  • the hypertension- related parameter may include a mean arterial pressure measurement.
  • the hypertension-related parameter may include a pulse pressure measurement.
  • the hypertension-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the hypertension-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the hypertension-related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the hypertension-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hypertension-related parameter is decreased by no more than about 10%, as compared to prior to administration.
  • the hypertension-related parameter 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 95%, as compared to prior to administration. In some embodiments, the hypertension-related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subj ect in an effective amount decreases a glaucoma-related parameter such as an adverse glaucoma-related parameter.
  • the glaucoma-related parameter may include an intraocular pressure measurement.
  • the glaucoma-related parameter may include a cup-disc ratio.
  • the glaucoma related parameter may include optic nerve head cupping.
  • the glaucoma-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the glaucoma-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is decreased by no more than about 10%, as compared to prior to administration.
  • the glaucoma-related parameter 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 95%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount increases a glaucoma- related parameter such as a protective or beneficial glaucoma-related parameter.
  • the glaucoma-related parameter may include a retinal nerve fiber layer (RNFL) thickness.
  • the glaucoma related parameter may include optic nerve head cupping.
  • the glaucoma-related parameter is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the glaucoma-related parameter is increased by about 10% or more, as compared to prior to administration.
  • the glaucoma-related parameter 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, or about 95%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration.
  • the glaucoma-related parameter is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter 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 95%, as compared to prior to administration.
  • the glaucoma-related parameter is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the glaucoma-related parameter is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the glaucoma-related parameter is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a macular degeneration/diabetic retinopathy-related parameter such as an adverse macular degeneration/diabetic retinopathy-related parameter.
  • the macular degeneration/diabetic retinopathy -related parameter may comprise a macular degeneration-related parameter.
  • the macular degeneration/diabetic retinopathy -related parameter may comprise a diabetic retinopathy-related parameter.
  • the macular degeneration/diabetic retinopathy -related parameter may include a RPE pigmentation and reflectivity measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a drusen measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a macular hemorrhage measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a choroidal neovascularization measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a edema measurement.
  • the macular degeneration/diabetic retinopathy -related parameter may include a microaneurysm measurement.
  • the macular degeneration/diabetic retinopathy -related parameter may include a intraretinal hemorrhage measurement.
  • the macular degeneration/diabetic retinopathy - related parameter may include a macular ischemia measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a neovascularization measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a vitreous hemorrhage measurement.
  • the macular degeneration/diabetic retinopathy-related parameter may include a traction retinal detachment measurement.
  • the macular degeneration/diabetic retinopathy -related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy -related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy -related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy-related parameter is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy -related parameter 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 95%, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy -related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount increases a macular degeneration/diabetic retinopathy-related parameter such as a protective or beneficial macular degeneration/diabetic retinopathy-related parameter.
  • the macular degeneration/diabetic retinopathy-related parameter may include a retinal thickness measurement.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by about 10% or more, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy-related parameter 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, or about 95%, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy-related parameter is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the macular degeneration/diabetic retinopathy -related parameter 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 95%, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the macular degeneration/diabetic retinopathy-related parameter is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a metabolic disorder-related parameter.
  • the metabolic disorder comprises obesity.
  • the metabolic disorder comprises hyperlipidemia. In some embodiments, the metabolic disorder comprises hypertriglyceridemia. In some embodiments, the metabolic disorder comprises metabolic syndrome. In some embodiments, the metabolic disorder comprises diabetes. In some embodiments, the diabetes comprises type II diabetes.
  • the metabolic disorder-related parameter may include a hemoglobin A1C measurement.
  • the metabolic disorder-related parameter may include a body mass index (BMI) measurement.
  • the metabolic disorder-related parameter may include a body weight measurement.
  • the metabolic disorder-related parameter may include a waist circumference measurement.
  • the metabolic disorder-related parameter may include a hip circumference measurement.
  • the metabolic disorder- related parameter may comprise a waist-hip ratio (WHR).
  • the metabolic disorder-related parameter may comprise a body fat percentage.
  • the metabolic disorder-related parameter may comprise a blood glucose measurement.
  • the metabolic disorder-related parameter may comprise a glucose tolerance measurement.
  • the metabolic disorder-related parameter may comprise a insulin sensitivity measurement.
  • the metabolic disorder-related parameter may comprise a blood triglyceride measurement.
  • the metabolic disorder- related parameter may comprise a non-HDL cholesterol measurement.
  • the metabolic disorder-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the metabolic disorder- related parameter is decreased by about 10% or more, as compared to prior to administration.
  • the metabolic disorder-related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the metabolic disorder-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the metabolic disorder-related parameter is decreased by no more than about 10%, as compared to prior to administration.
  • the metabolic disorder -related parameter 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 95%, as compared to prior to administration. In some embodiments, the metabolic disorder- related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a liver disease-related parameter.
  • the liver disease comprises fibrotic liver disease.
  • the liver disease comprises liver fibrosis.
  • the liver disease comprises cirrhosis.
  • the liver disease comprises non-alcoholic fatty liver disease (NAFLD).
  • the liver disease- related parameter may include an aspartate aminotransferase (AST) measurement.
  • the liver disease- related parameter may include an alanine aminotransferase (ALT) measurement.
  • the liver disease-related parameter may include an AST/ ALT ratio.
  • the liver disease-related parameter may include a liver fat percentage measurement.
  • the liver disease-related parameter may include a liver fibrosis score.
  • the liver disease-related parameter may include aNAFLD activity score.
  • the liver disease-related parameter may include a blood gamma-glutamyl transferase (GGT) measurement.
  • GTT blood gamma-glutamyl transferase
  • the liver disease-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the liver disease-related parameter is decreased by about 10% or more, as compared to prior to administration.
  • the liver disease-related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the liver disease-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the liver disease-related parameter is decreased by no more than about 10%, as compared to prior to administration.
  • the liver disease-related parameter 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 95%, as compared to prior to administration. In some embodiments, the liver disease-related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a hair loss-related parameter.
  • the hair loss comprises androgenetic alopecia.
  • the hair loss-related parameter may include a hair count measurement.
  • the hair loss-related parameter may include a hair thickness measurement.
  • the hair loss-related parameter may include a hair density measurement.
  • the hair loss-related parameter is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the hair loss-related parameter is decreased by about 10% or more, as compared to prior to administration.
  • the hair loss- related parameter is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 95%, as compared to prior to administration. In some embodiments, the hair loss-related parameter is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair loss-related parameter is decreased by no more than about 10%, as compared to prior to administration.
  • the hair loss- related parameter 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 95%, as compared to prior to administration.
  • the hair loss-related parameter is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets SOS Ras/Rho guanine nucleotide exchange factor 2 (S0S2), wherein the oligonucleotide comprises a small interfering RNA (siRNA).
  • the composition comprises an oligonucleotide that targets S0S2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length.
  • the composition comprises a sense strand that is 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.
  • the sense strand may be 14-30 nucleosides in length.
  • the composition comprises an antisense strand is 12-30 nucleosides in length.
  • the composition comprises an antisense strand that is 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.
  • the antisense strand may be 14-20 nucleosides in length.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of a full-length human S0S2 mRNA sequence such as SEQ ID NO: 11253.
  • At least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 11253.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of any one of SEQ ID NO: 1-5490, 11274-11303, or 11354-11383.
  • any of the aforementioned siRNAs may include an antisense strand that lacks a 5’ U of an antisense strand of one of SEQ ID NO 5491-10980, 11304-11333, or 11384-11413.
  • an siRNA comprises 15, 16, 17, 18, 19, 20, 21, or 22 contiguous bases of SEQ ID NO 5491-10980, 11304-11333, or 11384-11413.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex.
  • the first base pair of the double-stranded RNA duplex is an AU base pair.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human S0S2 mRNA.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human S0S2 mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in anon-human primate S0S2 mRNA.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a20mer, a21mer, a22mer, a23mer, a24mer, or a25mer in anon-human primate S0S2 mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human S0S2 mRNA, or a combination thereof.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, and 18mer, a 19mer, a20mer, a21mer, a22mer, a23mer, a24mer, or a25mer in a human S0S2 mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human S0S2 mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human S0S2 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human S0S2 mRNA and less than or equal to 30 human off -targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human S0S2 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human S0S2 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human S0S2 mRNA and less than or equal to 10 human off -targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human S0S2 mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human S0S2 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand.
  • the siRNA binds with a human S0S2 mRNA and less than or equal to 40 human off -targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human S0S2 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human S0S2 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18).
  • siRNA binds with a human S0S2 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18).
  • the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-5490.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1-5490, at least 80% identical to any one of SEQ ID NOs: 1-5490, at least 85% identical to of any one of SEQ ID NOs: 1-5490, at least 90% identical to any one of SEQ ID NOs: 1-5490, or at least 95% identical to any one of SEQ ID NOs: 1- 5490.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-5490, 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: 1-5490, 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: 1-5490.
  • 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 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 the aforementioned sequences.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise an overhang.
  • the sense strand may comprise a lipid moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11274-11303.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11274-11303, at least 80% identical to any one of SEQ ID NOs: 11274-11303, at least 85% identical to of any one of SEQ ID NOs: 11274-11303, at least 90% identical to any one of SEQ ID NOs: 11274-11303, or at least 95% identical to any one of SEQ ID NOs: 11274-11303.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11274-11303, 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: 11274-11303, 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: 11274-11303.
  • 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 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 the aforementioned sequences.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise an overhang.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID Nos: 11274-11303.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID Nos: 11354-11383.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11354-11383, at least 80% identical to any one of SEQ ID NOs: 11354-11383, at least 85% identical to of any one of SEQ ID NOs: 11354-11383, at least 90% identical to any one of SEQ ID NOs: 11354-11383, or at least 95% identical to any one of SEQ ID NOs: 11354-11383.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11354-11383, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11354-11383, 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: 11354-11383.
  • 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 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 the aforementioned sequences.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise an overhang.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID Nos: 11354-11383. [0043] In any of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5 ’ nucleoside has been modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A, T, C, U, or G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1- 5460, 11274-11303, and 11354-11383 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A, T, C, U, or G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1- 5460, 11274-11303, and 11354-11383 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 13082-13402 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 1-5460, 11274- 11303, and 11354-11383 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to a T or U.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to a T or U.
  • position 1 (fromthe 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274- 11303, and 11354-11383 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274- 11303, and 11354-11383 is modified to an C.
  • position 14 (fromthe 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an C.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an C.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 5491-10980.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 5491-10980, at least 80% identical to any one of SEQ ID NOs: 5491-10980, at least 85% identical to of any one of SEQ ID NOs: 5491-10980, at least 90% identical to any one of SEQ ID NOs: 5491 -10980, or at least 95% identical to any one of SEQ ID NOs: 5491-10980.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 5491 -10980, 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: 5491-10980, 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: 5491-10980.
  • 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 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 the aforementioned sequences.
  • the antisense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of SEQ ID Nos: 5491 - 10980.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11304-11333.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11304-11333, at least 80% identical to any one of SEQ ID NOs: 11304-11333, at least 85% identical to of any one of SEQ ID NOs: 11304-11333, at least 90% identical to any one of SEQ ID NOs: 11304-11333, or at least 95% identical to any one of SEQ ID NOs: 11304-11333.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11304-11333, 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: 11304-11333, 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: 11304-11333.
  • 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 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 the aforementioned sequences.
  • the antisense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of SEQ ID Nos: 11304- 11333.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11384-11413.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11384-11413, at least 80% identical to any one of SEQ ID NOs: 11384-11413, at least 85% identical to of any one of SEQ ID NOs: 11384-11413, at least 90% identical to any one of SEQ ID NOs: 11384-11413, or at least 95% identical to any one of SEQ ID NOs: 11384-11413.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11384-11413, 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: 11384-11413, 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: 11384-11413.
  • 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 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 the aforementioned sequences.
  • the antisense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of SEQ ID Nos: 11384- 11413.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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 any one of a siRNA 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 an siRNA of subset A.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of any one of a siRNA 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 an siRNA of subset B.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset C.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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 any one of a siRNA of subset C.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset C.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset D.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of any one of a siRNA of subset D.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset D.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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 any one of a siRNA of subset E.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset E.
  • 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 any one of a siRNA 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 an siRNA of subset F.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset G.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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 any one of a siRNA of subset G.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset G.
  • 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 H.
  • 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 H.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset H, 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 H, 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 H.
  • 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 any one of a siRNA of subset H.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset H.
  • 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 I.
  • 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 I.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset I, 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 I, 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 I.
  • 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 any one of a siRNA of subset I.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset I.
  • 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 J.
  • 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 J.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset J, 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 J, 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 J.
  • 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 any one of a siRNA of subset J.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset J.
  • 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 K.
  • 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 K.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset K, 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 K, 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 K.
  • 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 any one of a siRNA of subset K.
  • Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of an siRNA of subset K.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • any of the aforementioned siRNAs may include an antisense strand of one of subset A-subset K (subsets A, B, C, D, E, F, G, H, I, J, and K) , 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 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 A-subset K.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A-subset K, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A-subset K, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A-subset K.
  • 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 in Table 28.
  • 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 in Table 28.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 28, 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 in Table 28, 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 in Table 28.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 32.
  • 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 in Table 32.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 32, 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 in Table 32, 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 in Table 32.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 35.
  • 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 in Table 35.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 35, 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 in Table 35, 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 in Table 35.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 38.
  • 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 in Table 38.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 38, 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 in Table 38, 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 in Table 38.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, at least 80% identical to any one of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, at least 85% identical to of any one of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, at least 90% identical to any one of SEQ ID NOs: 743,
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 743, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799, at least 80% identical to any one of SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799, at least 85% identical to of any one of SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 83
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 6233, 6234, 6526, 6546, 6668, 7011, 7638, 7641, 7642, 7648, 8109, 8372, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756, at least 80% identical to any one of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756, at least 85% identical to of any one of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890,
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 888, 1683, 1684, 1912, 1922, 1927, 1938, 2014, 2167, 2213, 2362, 2364, 2365, 2598, 2631, 2759, 2890, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246, at least 80% identical to any one of SEQ ID NOs: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246, at least 85% identical to of any one of SEQ ID NOs: 6378, 7173, 7
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 6378, 7173, 7174, 7402, 7412, 7417, 7428, 7504, 7657, 7703, 7852, 7854, 7855, 8088, 8121, 8249, 8380, 8721, 8749, 8823, 8977, 8981, 9076, 9077, or 9246.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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 arange 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 S0S2, 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 S0S2 mRNA sequence such as SEQ ID NO: 11253; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human S0S2 mRNA sequence such as SEQ ID NO: 11253; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleo
  • the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 11253.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage.
  • the oligonucleotide comprises a modified internucleoside linkage.
  • the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphor odi thioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • a phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur.
  • Modified intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside 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 S0S2, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers.
  • the oligonucleotide comprises no more than 18 modified internucleoside linkages.
  • the oligonucleotide comprises no more than 20 modified intemucleoside linkages.
  • the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside link
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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-methoxy ethyl, 2'-0-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'- methoxy ethyl group. In some embodiments, the modified nucleoside comprises a methoxy ethyl. In some embodiments, the modified nucleoside comprises a 2'-O-methoxyethyl group (“MOE”). For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’ -methoxyethyl thymine.
  • MOE 2'-O-methoxyethyl group
  • the modified nucleoside comprises 2'-O-methyl. In some embodiments, the modified nucleoside comprises a 2'-0-alkyl group. In some embodiments, the modified nucleoside comprises a 2'-C-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, 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'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'- O- aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof.
  • 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'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O- aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’ -fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.
  • the modified nucleoside comprises an unlocked nucleic acid.
  • An unlocked nucleic acid may comprise the following structure:
  • 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 phosphate mimic.
  • the phosphate mimic comprises methylphosphonate.
  • An example of a nucleotide that comprises a methylphosphonate is shown below: methylphosphonate 2’-O-Methyl Uridine).
  • the oligonucleotide comprises 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,
  • the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides.
  • the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide.
  • the composition comprises an RGD peptide.
  • the composition comprises an RGD peptide derivative.
  • the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide.
  • the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the oligonucleotide comprises an RGD peptide and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the RGD peptide 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).
  • the RGD peptide comprises an amino benzoic acid derived RGD.
  • 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.
  • the RGD peptide comprises multiple of such RGD peptides.
  • the RGD peptide may include 2, 3, or 4 RGD peptides.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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.
  • 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- methoxy ethyl.
  • the sense strand comprises at least a 2’ -fluoro modified nucleoside, a 2’-O-Methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the antisense strand is combination of 2’ -fluoro and 2’-O-Methyl modifications.
  • each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’ -fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the sense strand comprises at least a 2’ -fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), 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’ -O- methoxy ethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl.
  • all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, 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’ -fluoro- modified 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 all purine nucle
  • all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O- methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro.
  • all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all pyrimidine nucleosides comprise 2’ -O-meihyl, 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 S0S2, 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 S0S2, 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 S0S2, 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 S0S2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or trivalent branched linker.
  • the oligo may be attached to 1 , 2 or 3 GalNAcs through a bivalent or trivalent branched linker.
  • the GalNAc moiety may include 1, 2, 3, or more GalNAc molecules.
  • the GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the 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 purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines.
  • all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines.
  • 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’ -methyl modification may be included, and vice versa.
  • pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. 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’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’ -fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O- methyl 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-meihyl modified purines.
  • all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -O-meihyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines.
  • the oligonucleotide comprises a particular modification pattern.
  • position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification.
  • position 9 of a strand of the oligonucleotide is a pyrimidine
  • all purines in a strand of the oligonucleotide have a 2’OMe modification.
  • position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide.
  • both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.
  • 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[33), 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 av[33 or av[36).
  • 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 S0S2 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 MTRES1, 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.
  • position 9 of a strand of the oligonucleotide when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • 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.
  • 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine.
  • all purines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’- fluoro-modified pyrimidine, provided there are not three 2’ -fluoro-modified pyrimidines in a row.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • 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 deoxy ribonucleotides.
  • position nine of the sense strand comprises a 2’ -fluoro-modified purine.
  • all pyrimidines of the sense strand comprise 2’ -O-methyl modified purines.
  • 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’ -fluoro- modified purine, provided there are not three 2’ -fluoro-modified purine in a row.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides and unmodified deoxyribonucleotide. 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 purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro-modified pyrimidines in a row.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides.
  • all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all 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- modifed nucleotides.
  • all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro- modified nucleotides and unmodified deoxyribonucleotide.
  • the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’-end group.
  • the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein.
  • the 5’ -end group may be or include a 5 ’ -end phosphorothioate, 5 ’ -end phosphorodithioate, 5 ’ -end vinylphosphonate (5’-VP), 5 ’-end methylphosphonate, 5 ’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl.
  • the 5’-end group may comprise 5’-VP.
  • the 5’-VP comprises a trans- vinylphosphonate or cis-vinylphosphonate.
  • the 5 ’-end group may include an extra 5’ phosphate.
  • a combination of 5 ’-end groups may be used.
  • the oligonucleotide includes a negatively charged group.
  • the negatively charged group may aid in cell or tissue penetration.
  • the negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group.
  • the end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy -C-malonyl.
  • the end group may include an extra 5’ phosphate such as an extra 5’ phosphate.
  • a combination of end groups may be used.
  • the oligonucleotide includes a phosphate mimic.
  • the phosphate mimic comprises vinyl phosphonate.
  • the vinyl phosphonate comprises a trans- vinylphosphonate.
  • the vinyl phosphonate comprises a cis-vinylphosphonate.
  • the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.
  • the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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 S0S2, 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 S0S2, 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.
  • the sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand.
  • LRP lipoprotein receptor related protein
  • TfR transferrin receptor
  • Mannose receptor ligand mannose receptor ligand
  • glucose transporter protein and LDL receptor ligand.
  • LDL receptor ligand LDL receptor ligand
  • Representative example of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA.
  • the GalNAc moiety is ETL17.
  • Representative example of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, 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.
  • a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and/or an antisense strand of a siRNA). In some embodiments, ahydrophobic 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 SOS, 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 of the following structure: . In some embodiments, the oligonucleotide comprises any aspect of the following structure: 5' oligonucleotide . In some embodiments, the oligonucleotide comprises any aspect of the following structure: . In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group.
  • the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.
  • the lipid includes a fatty acid.
  • the lipid comprises a lipid depicted in Table 1.
  • the example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety.
  • a lipid moiety in Table 1 may be attached at a different point of attachment than shown.
  • the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end.
  • the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.
  • the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.
  • the hydrophobic moiety may include a linker that comprises a carbocycle.
  • the carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl.
  • the linker may include a phenyl.
  • the linker may include a cyclohexyl.
  • the lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide.
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration).
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration).
  • the lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.
  • the lipid moiety may comprise or consist of the following structure: In some embodiments, the lipid moiety comprises or consists of the following structure: In some embodiments, the lipid moiety comprises the following structure: embodiments, the lipid moiety comprises or consist of the following structure: In some embodiments, the dotted line indicates a covalent connection.
  • the covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand.
  • n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • n is 5. In some embodiments, 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 phosphorami dite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol.
  • the phosphorami dite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate.
  • Some examples of phosphorami dite reagents that may be used to produce a hydrophobic conjugate are provided as follows: some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • Ris 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 phosphorami dite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety.
  • the phosphorami dite 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 modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition.
  • the modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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., anN-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 S0S2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or trivalent branched linker.
  • the oligo may be attached to 1 , 2 or 3 GalNAcs through a bivalent or trivalent branched linker.
  • the GalNAc moiety may include 1, 2, 3, or more GalNAc molecules.
  • the GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, 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 S0S2, 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 C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;
  • 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(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O-)O-,
  • 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, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, - N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 .
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2.
  • Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2.
  • 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 - NR 7 .
  • 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)(Q-)O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(Q- )S-, and -OP(OR 7 )O-.
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(O )O-, -OP(S)(O)O-, -OP(O)(S )O-, and -OP(OR 7 )O- In some embodiments, R 1 is selected from -OP(O)(OR 7 )O- and -OPCOR 7 ) ⁇ -.
  • 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 .
  • R 4 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2.
  • R 4 is selected from -OR 7 - and - OC(O)R 7 .
  • R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , - N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and - N(R 7 )C(O)R 7 .
  • each R 7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH.
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O- , and -OP(OR 7 )O-;
  • R 2 is Ci alkyl substituted with -OH or -OC(O)CH3;
  • R 3 is -OH or -OC(O)CH 3 ;
  • R 4 is -OH or -OC(O)CH 3 ;
  • R 5 is -NH(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 internucleoside linkages.
  • the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphorami date, 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: .
  • J may include one or more additional phosphates, or one or more phosphorothi oates 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. [00132] Some embodiments include the following, where J is the oligonucleotide: 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 “ETL17,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothi oates 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 phosphorothi oates 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: 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: may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide:
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide:
  • 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 phosphorothi oates 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.
  • 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 phosphor othi oates 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 phosphorothi oates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:
  • 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 phosphorothi oates 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.
  • R 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) 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 O: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphor othioate 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 phosphor othioate 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 The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphor othi oates 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.
  • 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. [00163] 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 phosphor othioate 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 phosphor othi oates 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 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 “[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.
  • [00175] 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.
  • 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 the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS:
  • Nf ’ is a 2’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphate or phosphorothioate linkage
  • the sense strand comprises modification pattern 2S: 5'- nsnsnnNfnNfNfNfnnnnnnnnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 4S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 5S: 5'- nsnsnnNfnNfNfNfnnnnnnnnsnsnN-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 6S: 5'-nnnnnnNfNfnNfnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 7S: 5'- nnrmrmnNfNfNfNfnnnnnnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 8S: 5'-nnnnnnNfnNfnNfnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’ -fl uoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 9S: 5'- nnnnnNfnNfNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern IOS: 5'-nrmnrmNfNfNfNfnnnnnnnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 1 IS: 5'-nnnrmnNfNfNfNfNfnnnnnnsn-3', wherein “Nf’ is a 2’ -fl uoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 12S: 5'-nnnnnNfnnNfnNfnnnnnnnsnsn- 3', wherein “Nf’is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 13S: 5'-nnnnNfnnNfNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 14S: 5'-nnnnnNfnNfNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 15S: 5'-nnnnnNfnNfNfnNfnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 16S: 5'- nnnnNfnNfNfNfNfnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 17S: 5NinnnnNlNfnNfnnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 18S: 5'-nnnnnNlNfnNfnNfnnnnnnnsnsn-3'. wherein “Nf ’ is a 2 ’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 19S: 5'-nnnnNfNfnNfNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 20S: 5'-nnnnnNfNfNfNfnnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 21 S: 5'- nnrmnNfNfNfNfnNfnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 22S: 5'-nnnnNfNfNfNfNfnnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 23S: 5'-nnnnNfnnnNfnNfnnnnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 24S: 5NinnnNfnnnNlNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 25S: 5NinnnNfnnNlNfnnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 26S: 5'-nnnnNfnnNfNfnNfnnnnnnnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 27S: 5'-nnnnNfnnNfNfNfNfnnnnnnnsn-3'.
  • Nf is a 2’ -fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 28S: 5NinnnNfnNfnNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 29S: 5NinnnNfnNfnNfnNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 30S: 5'-nnnnNfnNfnNlNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 3 IS: 5'-nnnnNfnNfNfNfNfnnnnnnnsn-3'.
  • Nf ’ is a 2’ -fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 32S: 5NinnnNlNfnnNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 33S: 5NinnnNlNfnnNfnNfnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 34S: 5'-nnnnNfNfnnNfNfnnnnnnnnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 35S: 5'-nnnnNfNfnNfNfnnnnnnnnsnsn-3'.
  • Nf ’ is a 2’ -fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 36S: 5'- nnrmNfNfnNfNfnNfnnnnnnsn-3', wherein “Nf ’ is a 2 ’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 37S: 5'-nrmnNfNfNfNfNfnrmnnnnnnsn-3', wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 38S: 5'-nnnrmnrmNfNfnrmnnnnrinsnsn-3', wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 39S: 5'-nnnnnnnNfnNfnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 40S: 5'-nnnrmnrmNfnrmnrmnrmnsnsn- wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 41 S: 5'- snnnnnNfnNlNfnnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 42S: 5'- snnnnNfnNfnNfnnnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 43 S: 5'- snnnnnnNfnNfnNfnnnnnnnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 44S: 5'- snnnnNfnNlNfdNNfnnnnnnnnsnsn-3'.
  • Nf is a 2 ’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • dN comprises a deoxy nucleoside
  • s is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 45S: 5'- snnnnnNfnnNfnNfnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 46S: 5'- snrmnNfNfNfNfNfnrmnnnnnnsn-3', wherein “Nf ’ is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 47S: 5'- snnnnNfnnNfNfNfNfnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 48S: 5'- snnnnNfNfnnNfNfnnnnnnnnsn-3'.
  • the sense strand comprises modification pattern 49S: 5'- snnnnNfnNfnNfNfnnnnnnnsn-3'. wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 50S: 5'- snnnnnNfNfNfNfnNfnnnnnnnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 5 IS: 5'- snnnnnNfnnNfNfnnnnnnnnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 52S: 5'- snnnnnnNfNfNINfnnnnnnnnsnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 53 S: 5'- snnnnNfnnnNfNfnnnnnnnnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 54S: 5'- snnnnnNfNfnNfNfnnnnnnnnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 55 S: 5'- snnnnNfnNfNfdNnNfnnnnnnnsnsn -3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “dN” comprises a deoxy nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 56S: 5'- snnnnNfnnnNfnNfnnnnnnnsn -3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 57S: 5'- snnnnNINfnnNfnnnnnnnnnsnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 58S: 5'- snnnnNfnnNINfnNfnnnnnnnsnsn -3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the sense strand comprises modification pattern 59S: 5’- snnnnmnNfNfNfnnnmnnnnnnnsn-3'.
  • Nf ’ is a 2’-fluoro-modified nucleoside
  • n is a 2’- O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O- methoxy ethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the sense strand comprises modification pattern 60S: 5’- snnnnmnNfNfNfnnnmnnnnnnnnsn-3'.
  • Nf ’ is a 2’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O-methoxyethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the nm is a 2’-O-methoxyethyl modified thymine.
  • the sense strand comprises modification pattern 61 S: 5’- snnnNmnNfNfNfNfnnnnNmnnnnnnsn-3'.
  • Nf is a2’-fluoro-modified nucleoside
  • n is a 2’- O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O- methoxy ethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the sense strand comprises modification pattern 62S: 5’- snnnnnmNfNfNfNfnnnmnnnnnnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “nm” is a 2’-O-methoxyethyl modified nucleoside, and N comprises one or more nucleosides.
  • the sense strand comprises modification pattern 63S: 5’- snnnnnmNfNfNfNfnnnmnnnnnnnsn-3'.
  • Nf ’ is a 2’-fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O-methoxyethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the nm is a2’-O-methoxyethyl modified thymine.
  • the sense strand comprises modification pattern 64S: 5’- snnnnnmNfNfNfNfnnnnmnnnnnsn-3'.
  • Nf ’ is a 2’- fluoro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O-methoxyethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the nm is a 2’-O-methoxyethyl modified thymine.
  • the nm is a2’-O-methoxyethyl modified thymine. In some embodiments, the nm is a2’-O- methoxy ethyl modified thymine.
  • the sense strand comprises modification pattern 65S: 5’- snrmnrnnNfNfNfNfnnmnnnnnnsn- 3’, wherein “Nf ’ is a2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “nm” is a 2’-O- methoxy ethyl modified nucleoside, and N comprises one or more nucleosides.
  • the nm is a 2’-O-methoxyethyl modified thymine. In some embodiments, the nm is a 2’-O-methoxyethyl modified thymine. In some embodiments, the sense strand comprises modification pattern 66S: 5’- snnnnmnNfNfNfNfnnnnnmnnnnnsn-3'.
  • Nf ’ is a 2’-fluoro-modified nucleoside
  • n is a 2’- O-methyl modified nucleoside
  • s is a phosphorothioate or phosphate linkage
  • nm is a 2’-O- methoxy ethyl modified nucleoside
  • N comprises one or more nucleosides.
  • the nm is a 2’-O-methoxyethyl modified thymine.
  • the nm is a 2’-O-methoxyethyl modified thymine.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS:
  • the antisense strand comprises modification pattern 2AS: 5'- nsNfsnnnNfnNfnNfnnnNfnNfnnsnsnsn-3'.
  • the antisense strand comprises modification pattern 3 AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnsnsn-3', wherein “Nf’ is a 2’ -fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 5 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'.
  • the antisense strand comprises modification pattern 6AS:5'-nsnsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 7AS:5'-nsNfsnnnNfnNfnnnnnnNfnNfnnsnsn-3' , wherein “Nf’ is a 2’-fhroro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 8AS:5’-nsNfsnnnNfnNfnNfiiNfnNfnNfnNfnsnsn-3’ , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 9AS:5’-nsNfsnNfnnNfnNlhnnnNlhNfnNlhsnsn-3' , wherein “Nf ’ is a 2’ -fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 10AS:5’-nsNfsnNfnnNfnnNfhNfnNfnNfhNfnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 10AS:5’-nsNfsnNfnnNfnnNfnnNfhNfnNfnNfhNfnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern
  • Nf is a 2’ -fhroro-modified nucleoside
  • n is a 2’-O-methyl modified nucleoside
  • s is a phosphate or phosphorothioate linkage
  • the antisense strand comprises modification pattern 12AS:5’-nsNfsnnnNfnNfnNfnNfnNfnnsnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 12AS:5’-nsNfsnnnnNfnNfnNfnNfnNfnNfnnnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 12AS:5’-nsNfsnn
  • the antisense strand comprises modification pattern 14AS:5’-nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 15AS:5’-nsNfsnnNfnNfnNfnnnnNfnNfnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the antisense strand comprises modification pattern 16AS:5’- nsNfsnNfnNfnNfnNfnNfnNfnnsnsn-3' , wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2 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, 13AS, 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS.
  • the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 11 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 21S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 23 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 25 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 31 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 33 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 35 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 37S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 38S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 39S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 40S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 41 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 42S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 43 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 44S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 45 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 46S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 47S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 48S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 49S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 50S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 51 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 52S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 53 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 54S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 55 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 56S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 57S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 58S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 59S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 60S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 61S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 62S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern63 and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 64S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 65 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense strand comprises pattern 66S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS or 16AS.
  • the sense 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, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S,
  • the sense strand comprises modification pattern 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S .
  • the sense 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, 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, or 66S and the antisense strand comprises modification pattern IAS.
  • the sense strand comprises modification 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, 34S, 35S, 36S,
  • the antisense strand comprises modification pattern 2AS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S,
  • the sense strand comprises modification 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, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 4AS.
  • the sense 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, 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, or 66S and the antisense strand comprises modification pattern 5 AS.
  • the sense strand comprises modification 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, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 6AS.
  • the sense 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, 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, or 66S and the antisense strand comprises modification pattern 7 AS.
  • the sense strand comprises modification 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, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 8AS.
  • the sense 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, 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, or 66S and the antisense strand comprises modification pattern 9AS.
  • the sense strand comprises modification 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, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 10AS.
  • the sense 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, 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, or 66S and the antisense strand comprises modification pattern HAS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, MS, 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, or 66S and the antisense strand comprises modification pattern 12AS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, MS, 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, or 66S and the antisense strand comprises modification pattern BAS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, MS, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31 S, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 14AS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, MS, 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, or 66S and the antisense strand comprises modification pattern MAS.
  • the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, MS, 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, 61 S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises modification pattern 16AS.
  • the sense strand comprises modification pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, MAS, MAS or 16AS.
  • the antisense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, MAS or 16AS .
  • the antisense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, I IS, 12S, 13S, 14S, MS, 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, or 66S.
  • the sense strand or the antisense strand comprises modification pattern ASO1.
  • the oligonucleotide may include purines.
  • purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof.
  • the oligonucleotide may include pyrimidines.
  • purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’ -O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’ -fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’ -fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O- methyl 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’ -O-meihyl modified purines.
  • all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -0-meihyl 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.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine.
  • all purines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’flouro-modified pyrimidine, provided there are never three 2’ -fluoro-modified pyrimidines in a row.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotide.
  • position nine of the sense strand comprises a2’-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’flouro-modified pyrimidine, provided there are never 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’flouro-modified nucleotides and unmodified deoxy ribonucleotides.
  • position nine of the sense strand comprises a 2’ -fluoro-modified purine.
  • all pyrimidines of the sense strand comprise 2’ -O-methyl modified purines.
  • 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’flouro- modified purine, provided there are never three 2’ -fluoro-modified purine in a row.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’flouro-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’flouro-modified purines, provided there are never 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’flouro-modified nucleotides and unmodified deoxy ribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides.
  • all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2 ’-fluoro-modified purines.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all 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’flouro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides.
  • all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines.
  • the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’flouro- modified nucleotides and unmodified deoxyribonucleotides.
  • the sense strand comprises or consists of a sequence at least 75% identical to of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252, at least 80% identical to of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141- 11252, at least 85% identical to of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252, at least 90% identical to of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252, or at least 95% identical to of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252.
  • the sense strand comprises or consists of the sequence of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252, or a sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sequence of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sequence of any one of SEQ ID NOs: 10981-11000, 11021-11115, 11091-11115, or 11141-11252.
  • the sense strand is an unmodified version of a nucleic acid sequence described herein. In some embodiments, the sense strand has more or different sequence modifications than a nucleic acid sequence described herein.
  • the antisense strand comprises or consists of a sequence at least 75% identical to of any one of SEQ ID NOs: 11001-11020 or 11116-11140, at least 80% identical to of any one of SEQ ID NOs: 11001-11020 or 11116-11140, at least 85% identical to of any one of SEQ ID NOs: 11001-11020 or 11116-11140, at least 90% identical to of any one of SEQ ID NOs: 11001 -11020 or 11116-11140, or at least 95% identical to of any one of SEQ ID NOs: 11001-11020 or 11116-11140.
  • the antisense strand comprises or consists of the sequence of any one of SEQ ID NOs: 11001-11020 or 11116-11140 or a sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the sequence of any one of SEQ ID NOs: 11001-11020 or 11116-11140, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the sequence of any one of SEQ ID NOs: 11001 -11020 or 11116-11140. In some embodiments, the antisense strand is an unmodified version of a nucleic acid sequence described herein. In some embodiments, the antisense strand has more or different sequence modifications than a nucleic acid sequence described herein.
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Tables 15-25, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Tables 15-25. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 15, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 15. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 16. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 17, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 18, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 18. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 19, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 19.
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 20, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 20. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 21, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 21. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 22. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 23, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 22. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 23, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table
  • the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 24, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 24. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 25, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in Table 25.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Tables 15-25, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Tables 15- 25. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 15, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 15. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 16, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 16. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 17, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 17. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 18, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 18. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 19, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 19. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 20, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 20. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 21, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 21. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 22, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 22. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 23, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 23. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 24, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 24. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 25, or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed in Table 25.
  • the sense strand includes a nucleoside sequence of a sense strand in any of Tables 21-25 and omits an A, U, UU, or AUU.
  • a sense strand may omit a 3’ AUU of a sense strand sequence in any of Tables 21-25.
  • the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand sequence in any of Tables 21-25.
  • the sense strand comprises a sequence at least 80%, at least 85%, at least 90%, or at least 95% identical to the nucleoside sequence of positions 1-18 of a sense strand sequence in any of Tables 21-25.
  • the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand sequence in any of Tables 21-25, or a sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand sequence in any of Tables 21-25, or a sequence comprising 3 or 4 nucleoside substitutions, additions, or deletions.
  • a sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 21.
  • the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 21.
  • the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 21.
  • the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 21.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 21 omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 21 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • a sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 22.
  • the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 22.
  • the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 22.
  • the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 22.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 22 omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 22 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • a sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 23.
  • the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 23.
  • the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 23.
  • the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 23.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 23 omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 23 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • a sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 24.
  • the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 24.
  • the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 24.
  • the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 24.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 24 omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 24 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • a sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 25.
  • the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand in Table 25.
  • the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 25.
  • the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 25.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 25 omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 25 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • the antisense strand includes a nucleoside sequence of an antisense strand in any of Tables 21-25 and omits a U or UU.
  • an antisense strand may omit a 5’ U and a 3’ UU of an antisense strand sequence in any of Tables 21-25.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand sequence in any of Tables 21-25.
  • the antisense strand comprises a sequence at least 80%, at least 85%, at least 90%, or at least 95% identical to the nucleoside sequence of positions 2-19 of an antisense strand sequence in any of Tables 21-25.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand sequence in any of Tables 21-25, or a sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand sequence in any of Tables 21-25, or a sequence comprising 3 or 4 nucleoside substitutions, additions, or deletions.
  • An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 21.
  • the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 21.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 21.
  • the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 21.
  • the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 21 omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 21 and omits at least one nucleoside comprising a U or UU.
  • An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 22.
  • the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 22.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 22.
  • the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 22.
  • the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 22 omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 22 and omits at least one nucleoside comprising a U or UU.
  • An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 23.
  • the antisense strand comprises the nucleoside sequence of positions 1- 18 of an antisense strand in Table 23.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 23.
  • the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 23.
  • the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 23 omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 23 and omits at least one nucleoside comprising a U or UU.
  • An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 24.
  • the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 24.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 24.
  • the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 24.
  • the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 24 omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 24 and omits at least one nucleoside comprising a U or UU.
  • An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 25.
  • the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 25.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 25.
  • the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 25.
  • the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 25 omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table 25 and omits at least one nucleoside comprising a U or UU.
  • 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 in Table 27.
  • 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 in Table 27.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 27, 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 in Table 27, 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 in Table 27.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 31.
  • 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 in Table 31.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 31, 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 in Table 31, 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 in Table 31.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 34.
  • 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 in Table 34.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 34, 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 in Table 34, 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 in Table 34.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 37.
  • 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 in Table 37.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 37, 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 in Table 37, 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 in Table 37.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 10981-11000.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 10981 -11000, at least 80% identical to any one of SEQ ID NOs: 10981-11000, at least 85% identical to of any one of SEQ ID NOs: 10981-11000, at least 90% identical to any one of SEQ ID NOs: 10981-11000, or at least 95% identical to any one of SEQ ID NOs: 10981-11000.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 10981 -11000, 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: 10981 -11000, 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: 10981-11000.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11001-11020.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11001 -11020, at least 80% identical to any one of SEQ ID NOs: 11001-11020, at least 85% identical to of any one of SEQ ID NOs: 11001-11020, at least 90% identical to any one of SEQ ID NOs: 11001-11020, or at least 95% identical to any one of SEQ ID NOs: 11001-11020.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11001 -11020, 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: 11001-11020, 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: 11001-11020.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11021-11090.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11021 -11090, at least 80% identical to any one of SEQ ID NOs: 11021-11090, at least 85% identical to of any one of SEQ ID NOs: 11021-11090, at least 90% identical to any one of SEQ ID NOs: 1 -5490, or at least 95% identical to any one of SEQ ID NOs: 11021-11090.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11021 -11090, 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: 11021 -11090, 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: 11021-11090.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11091-11115.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11091 -11115, at least 80% identical to any one of SEQ ID NOs: 11091-11115, at least 85% identical to of any one of SEQ ID NOs: 11091-11115, at least 90% identical to any one of SEQ ID NOs: 11091-11115, or at least 95% identical to any one of SEQ ID NOs: 11091-11115.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11091 -11115, 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: 11091 -11115, 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: 11091-11115.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise a lipid moiety such as a cholesterol moiety described herein.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11116-11140.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11116-11140, at least 80% identical to any one of SEQ ID NOs: 11116-11140, at least 85% identical to of any one of SEQ ID NOs: 11116-11140, at least 90% identical to any one of SEQ ID NOs: 11116-11140, or at least 95% identical to any one of SEQ ID NOs: 11116-11140.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11116-11140, 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: 11116-11140, 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: 11116-11140.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11141-11252.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11141 -11252, at least 80% identical to any one of SEQ ID NOs: 11141-11252, at least 85% identical to of any one of SEQ ID NOs: 11141-11252, at least 90% identical to any one of SEQ ID NOs: 11141-11252, or at least 95% identical to any one of SEQ ID NOs: 11141-11252.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11141 -11252, 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: 11141 -11252, 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: 11141-11252.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11254-11263.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11254-11263, at least 80% identical to any one of SEQ ID NOs: 11254-11263, at least 85% identical to of any one of SEQ ID NOs: 11254-11263, at least 90% identical to any one of SEQ ID NOs: 11254-11263, or at least 95% identical to any one of SEQ ID NOs: 11254-11263.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11254-11263, 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: 11254-11263, 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: 11254-11263.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11264-11273.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11264-11273, at least 80% identical to any one of SEQ ID NOs: 11264-11273, at least 85% identical to of any one of SEQ ID NOs: 11264-11273, at least 90% identical to any one of SEQ ID NOs: 11264-11273, or at least 95% identical to any one of SEQ ID NOs: 11264-11273.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11264-11273, 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: 11264-11273, 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: 11264-11273.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11334-11343.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11334-11343, at least 80% identical to any one of SEQ ID NOs: 11334-11343, at least 85% identical to of any one of SEQ ID NOs: 11334-11343, at least 90% identical to any one of SEQ ID NOs: 11334-11343, or at least 95% identical to any one of SEQ ID NOs: 11334-11343.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11334-11343, 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: 11334-11343, 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: 11334-11343.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11344-11345.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11344-11345, at least 80% identical to any one of SEQ ID NOs: 11344-11345, at least 85% identical to of any one of SEQ ID NOs: 11344-11345, at least 90% identical to any one of SEQ ID NOs: 11344-11345, or at least 95% identical to any one of SEQ ID NOs: 11344-11345.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11344-11345, 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: 11344-11345, 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: 11344-11345.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11414-11443.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11414-11443, at least 80% identical to any one of SEQ ID NOs: 11414-11443, at least 85% identical to of any one of SEQ ID NOs: 11414-11443, at least 90% identical to any one of SEQ ID NOs: 11414-11443, or at least 95% identical to any one of SEQ ID NOs: 11414-11443.
  • the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11414-11443, 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: 11414-11443, 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: 11414-11443.
  • the sense strand may comprise a modification pattern described herein.
  • 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: 11444-11468.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11444-11468, at least 80% identical to any one of SEQ ID NOs: 11444-11468, at least 85% identical to of any one of SEQ ID NOs: 11444-11468, at least 90% identical to any one of SEQ ID NOs: 11444-11468, or at least 95% identical to any one of SEQ ID NOs: 11444-11468.
  • the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11444-11468, 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: 11444-11468, 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: 11444-11468.
  • the antisense strand may comprise a modification pattern described herein.
  • the antisense strand may comprise a lipid moiety.
  • the antisense strand may comprise a GalNAc moiety.
  • the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3’, wherein “dN” is any deoxynucleotide, “n” is a2’-O-methyl or 2’ O-methoxyeihyl-modified nucleoside, and “s” is a phosphate or phosphorothioate linkage.
  • the ASO comprises modification 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, 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, IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS.
  • the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. In some embodiments, the composition is formulated for ocular delivery.
  • 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 internucleoside linkages.
  • the oligonucleotide may include any modifications described herein, such as modifications from a base sequence.
  • the kit may include a delivery reagent such as a needle.
  • the kit may 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 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.
  • 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.
  • Some embodiments relate to a method of reversing a disorder a disorder in a subj ect in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.
  • 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.
  • 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). In some embodiments, the administration is intraperitoneal. In some embodiments, the administration is intraparenchymal.
  • the administration is intramuscular (e.g., by intramuscular injection).
  • the administration may be to an eye tissue (e.g., by intravitreal, intracameral or subconjunctival injection, or by topical administration to the eye).
  • the administration may be to a central nervous system tissue (e.g., brain or spinal cord or spinal canal).
  • the administration is intracerebroventricular or intrathecal (e.g., by intrathecal injection or infusion).
  • the administration may be to joint tissue (e.g., by intra-articular injection).
  • the administration may be to airway or lung tissue (e.g., by intranasal, intratracheal or inhaled administration).
  • the administration may be to skin or connective tissue (e.g., by topical administration or injection to the skin).
  • the pharmaceutical composition is for intraocular administration.
  • the pharmaceutical composition is for intravitreal administration.
  • Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection by means of a syringe, optionally a pen- like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump.
  • the formulation of the invention can also be adapted to transdermal administration, e.g., by needle-free injection or from a patch, optionally an iontophoretic patch, or transmucosal, e.g., buccal, administration.
  • composition of the invention may be administered in suitable dosage forms, for example, as solutions, suspensions, emulsions, tablets, coated tablets, capsules, hard gelatine capsules and soft gelatine capsules, drops, eye drops, ophthalmic ointments, ophthalmic rinses, injection solution, and the like.
  • Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject having the disorder.
  • the disorder is a chronic kidney disease, diabetic nephropathy, gout, hyperuricemia, hypertension, cerebrovascular disease, type 2 diabetes, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, glaucoma, ocular hypertension, retinal diseases, age-related macular degeneration, choroidal neovascularization, geographic atrophy, diabetic retinopathy, non-alcoholic fatty liver disease, fibrotic liver disease, liver fibrosis, cirrhosis, or hair loss disorder.
  • the disorder comprises a kidney disease. In some embodiments, the disorder comprises chronic kidney disease. In some embodiments, the disorder comprises diabetic nephropathy. In some embodiments, the disorder comprises gout. In some embodiments, the disorder comprises hyperuricemia. In some embodiments, the disorder comprises hypertension. In some embodiments, the disorder comprises cerebrovascular disease. In some embodiments, the disorder comprises a metabolic disorder. In some embodiments, the disorder comprises diabetes. In some embodiments, the disorder comprises type 2 diabetes. In some embodiments, the disorder comprises metabolic syndrome. In some embodiments, the disorder comprises obesity. In some embodiments, the disorder comprises hyperlipidemia. In some embodiments, the disorder comprises hypertriglyceridemia. In some embodiments, the disorder comprises glaucoma.
  • the disorder comprises ocular hypertension. In some embodiments, the disorder comprises retinal diseases. In some embodiments, the disorder comprises age-related macular degeneration. In some embodiments, the disorder comprises choroidal neovascularization. In some embodiments, the disorder comprises geographic atrophy. In some embodiments, the disorder comprises diabetic retinopathy. In some embodiments, the disorder comprises a liver disease. In some embodiments, the disorder comprises nonalcoholic fatty liver disease. In some embodiments, the disorder comprises fibrotic liver disease. In some embodiments, the disorder comprises liver fibrosis. In some embodiments, the disorder comprises cirrhosis. In some embodiments, the disorder comprises hair loss.
  • Some embodiments of the methods described herein include treatment of a subject.
  • subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
  • the subject is a vertebrate.
  • the subject is an animal.
  • the subject is a mammal.
  • the subject is a dog.
  • the subject is a cat.
  • the subject is a cattle.
  • the subject is a mouse.
  • the subject is a rat.
  • the subject is a primate.
  • the subject is a monkey.
  • the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female.
  • the subj ect has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers.
  • the subject is overweight.
  • the subject has a BMI of 25 or more.
  • the subject has a BMI of 25- 29.
  • the subject is obese.
  • the subject has a BMI of 30 or more.
  • the subject has a BMI of 30-39.
  • the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 25-50. [00240] In some embodiments, the subject is > 90 years of age. In some embodiments, the subject is > 85 years of age. In some embodiments, the subject is > 80 years of age. In some embodiments, the subject is > 70 years of age. In some embodiments, the subject is > 60 years of age. In some embodiments, the subject is > 50 years of age. In some embodiments, the subject is > 40 years of age. In some embodiments, the subject is > 30 years of age. In some embodiments, the subject is > 20 years of age. In some embodiments, the subject is > 10 years of age. In some embodiments, the subject is > 1 years of age. In some embodiments, the subject is > 0 years of age.
  • the subject is ⁇ 100 years of age. In some embodiments, the subject is ⁇ 90 years of age. In some embodiments, the subject is ⁇ 85 years of age. In some embodiments, the subject is ⁇ 80 years of age. In some embodiments, the subject is ⁇ 70 years of age. In some embodiments, the subject is ⁇ 60 years of age. In some embodiments, the subject is ⁇ 50 years of age. In some embodiments, the subject is ⁇ 40 years of age. In some embodiments, the subject is ⁇ 30 years of age. In some embodiments, the subject is ⁇ 20 years of age. In some embodiments, the subject is ⁇ 10 years of age. In some embodiments, the subject is ⁇ 1 years of age.
  • the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age.
  • a baseline measurement is obtained from the subject prior to treating the subject.
  • baseline measurements include a baseline glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGFR) measurement, a baseline creatinine measurement, a baseline blood urea nitrogen (BUN) measurement, a baseline proteinuria measurement, a baseline microalbuminuria measurement, a baseline blood urate measurement, a baseline urine albumin creatine ratio, a baseline systolic blood pressure (SBP) measurement, a baseline diastolic blood pressure (DBP) measurement, a baseline mean arterial pressure measurement, a baseline pulse pressure measurement, a baseline intraocular pressure (I OP) measuremait, a baseline cup-disc ratio, a baseline RNFL thickness measurement, a baseline optic nerve head cupping measurement, a baseline RPE pigmentation and reflectivity measurement, a baseline retinal thickness measurement,
  • the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject.
  • an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay
  • the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • the baseline measurement is obtained by PCR.
  • the baseline measurement is a baseline GFR or eGFR measurement.
  • the baseline measurement is a baseline GFR measurement.
  • the baseline measurement is a baseline eGFR measurement.
  • the baseline GFR or eGFR measurement may be indicated in units of volume per time (e.g., mL/min).
  • the baseline GFR measurement may be obtained using a baseline clearance measurement such as a baseline creatinine clearance measurement.
  • the baseline GFR may also be determined by injecting insulin, sinistrin, a radioactive tracer, or cy statin C, and determining a baseline clearance rate.
  • the baseline eGFR measurement may also be obtained using a clearance estimate such as an estimation of serum creatinine clearance.
  • the baseline GFR or eGFR may be 100-130 mL/min/1.73m 2 , 90-100 mL/min/1.73m 2 .
  • the baseline GFR or eGFR may be below 90 or 100 mL/min/1.73m 2 .
  • the baseline GFR or eGFR may be indicative of normal kidney function, CKD1, CKD2, CKD3, CKD4, or CKD5, as indicated by the following kidney function index:
  • the baseline measurement is a baseline creatinine measurement.
  • the baseline creatinine measurement is a baseline creatinine concentration.
  • the baseline creatinine measurement is a baseline circulating (e.g., serum or plasma) creatinine measurement.
  • the baseline creatinine measurement is a baseline urine creatinine measurement.
  • the baseline creatinine measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline circulating creatinine measurement may be about 0.5-1.3 mg/ dL.
  • the baseline creatinine may be measured in a fluid sample.
  • the baseline circulating creatinine measurement may be above 1.3 mg/dL.
  • the baseline circulating creatinine measurement may be within, above, or below a reference range.
  • the baseline urine creatinine measurement may be within, above, or below a reference range.
  • Typical human reference ranges for serum creatinine are 0.5 mg/dL to 1.0 mg/dL for women or 0.7 mg/dL to 1.2 mg/dL for men. The significance of a single creatinine value may be interpreted in light of the patient's muscle mass. A patient with a greater muscle mass may have a higher creatinine concentration.
  • a baseline serum creatinine of 2.0 mg/dL may indicate normal kidney function in a male body builder
  • a serum creatinine of 1.6 mg/dL may indicate significant renal disease in an elderly female.
  • Males may typically produce approximately 150 pmol to 200 pmol of creatinine per kilogram of body weight per 24 h while females may produce approximately 100 pmol/kg/24 h to 150 pmol/kg/24 h. In normal circumstances, all this daily creatinine production is excreted in the urine, which may be included in a baseline urine creatinine measurement.
  • the baseline measurement is a baseline blood urea nitrogen (BUN) measurement.
  • the baseline BUN measurement is a baseline BUN concentration.
  • the baseline BUN measurement is a baseline circulating BUN measurement.
  • the baseline BUN measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline BUN is 6-20 mg/dL.
  • the baseline BUN is over 20 mg/dL.
  • a normal BUN range is 6-20 mg/dL.
  • the baseline measurement is a baseline BUN/creatinine ratio.
  • the baseline measurement is a baseline proteinuria measurement.
  • “Proteinuria” may describe an increase (e.g., a moderate increase) in a level of urine protein.
  • the baseline proteinuria measurement may be indicated as a concentration, a ratio, or a mass/unit time (e.g., mg/mmol urine, protein/creatinine, or mg protein/hr).
  • the baseline proteinuria measurement includes a baseline proteinuria concentration.
  • the baseline proteinuria measurement is a baseline urine protein measurement.
  • the baseline proteinuria measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline proteinuria measurement is indicative of proteinuria in the subject. Proteinuria can be diagnosed from a 24-hour urine collection or, from an elevated concentration in a spot sample. In some embodiments, the baseline measurement is a baseline urine protein/creatinine ratio.
  • the baseline measurement is a baseline microalbuminuria measurement.
  • “Microalbuminuria” may describe an increase (e.g., a moderate increase) in a level of urine albumin.
  • the baseline microalbuminuria measurement may be indicated as a concentration, a ratio, or a mass/unit time (e.g., mg/mmol urine, albumin/ creatinine, or mg albumin/hr).
  • the baseline microalbuminuria measurement includes a baseline microalbuminuria concentration.
  • the baseline microalbuminuria measurement is a baseline urine microalbuminuria measurement.
  • the baseline microalbuminuria measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline microalbuminuria measurement is indicative of microalbuminuria in the subject.
  • Microalbuminuria can be diagnosed from a 24-hour urine collection (between 30-300 mg/24 hours) or, from an elevated concentration in a spot sample (20 to 200 mg/1).
  • the baseline measurement is a baseline urine albumin/creatinine ratio.
  • the baseline microalbuminuria measurement may include a microalbuminuria measurement within a range or amount defined in Table 2.
  • the baseline measurement is a baseline blood urate measurement.
  • the baseline blood urate measurement is a baseline blood urate concentration.
  • the baseline blood urate measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline blood urate measurement is indicative of hyperuricemia. Serum uric acid concentrations greater than 6 mg/dL (e.g., for females), greater than 7 mg/dL (e.g., for men), or greater than 5.5 mg/dL (e.g., for a subject under 18 years old) may be indicative of hyperuricemia.
  • Some embodiments of the methods described herein include obtaining the baseline measurement of the subject by measuring blood pressure (e.g., systolic or diastolic) with a sphygmomanometer in which a healthcare professional places a cuff around an arm of the subject and inflates the cuff with a pump until the circulation is cut off. A small valve slowly deflates the cuff, and the healthcare professional measures the pressure with the aid of a stethoscope that is placed over the arm of the subject in order to listen for the sound of the blood pulsing through the arteries.
  • blood pressure e.g., systolic or diastolic
  • the first measurement in which blood rushes is the systolic blood pressure (SBP), and after the sound fades, the second number indicates the diastolic blood pressure (DBP), which is a measure the blood pressure of the heart at rest.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • the mean arterial pressure (MAP) is an average blood pressure of the subject during a single cardiac cycle.
  • the MAP can be measured directly using methods such as applanation tonometry or it can be approximated by using a formula in which the diastolic blood pressure is doubled and added to the systolic blood pressure and that composite sum is then divided by 3 to estimate MAP.
  • the pulse pressure can be calculated by subtracting the systolic pressure from the diastolic pressure.
  • the baseline measurement is a baseline systolic blood (SBP) pressure measurement.
  • the baseline SBP measurement is measured in mm of mercury (mm Hg).
  • the SBP measurement is obtained with a sphygmomanometer.
  • the baseline SBP measurement may be indicative of normal blood pressure. For most adults, normal SBP at rest is within the range of 100-130 mmHg. For most adults, hypertension is present if the resting blood pressure is persistently at or above 130/80 or 140/90 mmHg.
  • the baseline SBP measurement may be indicative of hypertension (e.g., at least 130 mmHg, or at least 140 mmHg).
  • the baseline SBP measurement may include a baseline cerebral SBP measurement.
  • the baseline measurement is a baseline diastolic blood (DBP) pressure measurement.
  • the baseline DBP measurement is measured in mm Hg.
  • the DBP measurement is obtained with a sphygmomanometer.
  • the baseline DBP measurement may be indicative of normal blood pressure. For most adults, normal DBP at rest is within the range of 60-80 mmHg.
  • the baseline DBP measurement may be indicative of hypertension (e.g., at least 80 mmHg, or at least 90 mmHg).
  • the baseline DBP measurement may include a baseline cerebral DBP measurement.
  • the baseline measurement is a baseline mean arterial pressure (MAP).
  • the baseline MAP is measured in mm of mercury (mm Hg).
  • the MAP measurement is obtained with a sphygmomanometer.
  • the baseline MAP may be indicative of normal blood pressure. For most adults, MAP at rest is in a range of 70-100 mmHg.
  • the baseline MAP measurement may be indicative of hypertension (e.g., greater than 100 mmHg).
  • the baseline measurement is a baseline pulse pressure.
  • the baseline pulse pressure is measured in mm of mercury (mm Hg).
  • the pulse pressure measurement is obtained with a sphygmomanometer.
  • the baseline pulse pressure may be indicative of normal blood pressure. For most adults, normal pulse pressure at rest is less than 40 mmHg.
  • the baseline pulse pressure may be indicative of hypertension (e.g., at least 50 mm Hg or at least 60 mm Hg).
  • the baseline measurement is a baseline intraocular pressure (IOP) measurement.
  • the baseline IOP may be measured using a tonometer.
  • the baseline IOP measurement may be in millimeters of mercury (mmHg).
  • the baseline IOP measurement may be indicative of a normal IOP.
  • the baseline IOP measurement may be indicative of abnormal or high IOP.
  • a normal IPO measurement may be between 10 mmHg and 20 mmHg.
  • the baseline IOP measurement may be above 20 mmHg.
  • the baseline measurement is a baseline measurement of optic nerve head cupping.
  • the baseline measurement of optic nerve head cupping may be a cup-disc ratio measurement.
  • the baseline cup-disc ratio may be measured using a slit lamp.
  • the baseline cup-disc ratio measurement may be indicative of a normal cup-disc ratio.
  • the baseline cup-disc ratio measurement may be indicative of a high or abnormal cup-disc ratio.
  • a normal cup-disc ratio measurement may be between 0.4 and 0.8.
  • the baseline cup-disc ratio measurement may be above 0.8.
  • the baseline measurement is a baseline retinal nerve fiber layer (RNFL) thickness measurement.
  • the baseline RNFL thickness may be measured using optical coherence tomography.
  • the baseline RNFL thickness measurement may be in pm.
  • the baseline RNFL thickness measurement may be indicative of a normal RNFL thickness measurement.
  • the baseline RNFL thickness measurement may be indicative of a low or abnormal RNFL thickness measurement.
  • a normal RNFL thickness measurement may be around 100 pm.
  • the baseline RNFL thickness measurement may be below 90 pm.
  • the baseline measurement is a baseline retinal thickness measurement.
  • the baseline retinal thickness may be measured using optical coherence tomography.
  • the baseline retinal thickness measurement may be in pm.
  • the baseline retinal thickness measurement may be indicative of a normal retinal thickness measurement.
  • the baseline retinal thickness measurement may be indicative of a high or abnormal retinal thickness measurement.
  • a normal retinal thickness measurement may be about 190 pm to 250 pm.
  • the baseline retinal thickness measurement may be above 250 pm.
  • the baseline measurement is a baseline edema measurement.
  • the baseline edema may be measured using optical coherence tomography.
  • the baseline edema measurement may be in pm.
  • the baseline edema measurement may be indicative of a normal edema measurement.
  • the baseline edema measurement may be indicative of a high or abnormal edema measurement.
  • a normal edema measurement may be between 190 pm and 250 pm.
  • the baseline edema measurement may be above 250 pm.
  • the baseline measurement is a baseline RPE pigmentation and reflectivity measurement.
  • the baseline RPE pigmentation and reflectivity measurement may be measured using optical coherence tomography.
  • the baseline RPE pigmentation and reflectivity measurement may be indicative of a normal RPE pigmentation and reflectivity measurement.
  • the baseline RPE pigmentation and reflectivity measurement may be indicative of abnormal RPE pigmentation and reflectivity.
  • the baseline measurement is a baseline drusen measurement.
  • the baseline drusen may be measured using an eye exam or retinal photography.
  • the baseline drusen measurement may be the size of the drusen or the number of the drusen.
  • the baseline drusen measurement may be indicative of a normal drusen measurement.
  • the baseline drusen measurement may be indicative of a high or abnormal drusen measurement.
  • the baseline measurement is a baseline hemorrhage measurement.
  • the baseline hemorrhage measurement may be a vitreous hemorrhage.
  • the baseline hemorrhage measurement may be an intraretinal hemorrhage.
  • the baseline hemorrhage may be a macular hemorrhage.
  • the baseline hemorrhage may be measured using retinal photography.
  • the baseline hemorrhage measurement may be indicative of a normal hemorrhage measurement.
  • the baseline hemorrhage measurement may be indicative of an abnormal or high hemorrhage measurement.
  • the baseline measurement is a baseline macular ischemia measurement.
  • the baseline macular ischemia may be measured using fluorescein angiography or optical coherence tomography angiography.
  • the baseline macular ischemia measurement may be a measurement of the foveal avascular zone.
  • the baseline macular ischemia measurement may be indicative of a normal macular ischemia measurement.
  • the baseline macular ischemia measurement may be indicative of a high or abnormal macular ischemia measurement.
  • a normal foveal avascular zone measurement may have a diameter between 0.5 mm to 0.6 mm.
  • the baseline foveal avascular zone measurement may have a diameter above 0.6 mm.
  • the baseline measurement is a baseline microaneurysm measurement.
  • the baseline microaneurysm may be measured using fluorescein angiography.
  • the baseline microaneurysm measurement may be the count of microaneurysms.
  • the baseline microaneurysm measurement may be indicative of a normal microaneurysm measurement.
  • the baseline microaneurysm measurement may be indicative of high or abnormal microaneurysm measurement.
  • the baseline measurement is a baseline neovascularization measurement.
  • the baseline neovascularization measurement may be a choroidal neovascularization measurement.
  • the baseline neovascularization measurement may be measured using imaging techniques such as fluorescein angiography.
  • the baseline neovascularization measurement may be an area of the neovascularization.
  • the baseline neovascularization measurement may be indicative of a normal neovascularization measurement.
  • the baseline neovascularization measurement may be indicative of a high or abnormal neovascularization measurement.
  • the baseline measurement is a baseline traction retinal detachment measurement.
  • the baseline traction retinal detachment may be measured using imaging techniques, including optical coherence tomography.
  • the baseline traction retinal detachment measurement may be indicative of a normal retina.
  • the baseline traction retinal detachment measurement may be indicative of macular degeneration or diabetic retinopathy.
  • the baseline measurement is a baseline hemoglobin A1C measurement.
  • the baseline hemoglobin A1C measurement is a baseline hemoglobin A1C concentration.
  • the baseline hemoglobin A1C measurement is a baseline circulating hemoglobin A1C measurement.
  • the baseline hemoglobin A1C measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or HPLC.
  • the baseline hemoglobin A1C measurement may be indicative of a healthy normal A1C measurement.
  • the healthy normal hemoglobin A1C measurement may be below 48 mmol/mol (6.5 DCCT %).
  • the healthy normal hemoglobin A1C measurement may be below 53 mmol/mol (7.0 DCCT %).
  • the baseline hemoglobin A1C measurement may be indicative of diabetes of pre-diabetes.
  • a baseline hemoglobin A1C measurement above 48 mmol/mol, or above 53 mmol/mol may indicate diabetes of pre-diabetes.
  • the baseline hemoglobin A1C measurement may be indicative of diabetes.
  • the baseline hemoglobin A1C measurement may be indicative of pre-diabetes. In some cases, the baseline hemoglobin A1C measurement is below 5.7 DCCT % (e.g., indicative of anormal healthy diagnosis).
  • the baseline hemoglobin Al C measurement is between 5.7 and 6.4 DCCT % (e.g., indicative of prediabetes). In some cases, the baseline hemoglobin A1C measurement is above 6.4 DCCT % (e.g., indicative of diabetes).
  • the baseline measurement is a baseline body mass measurement.
  • the baseline body mass measurement is a baseline body mass index (BMI).
  • BMI may be defined as a body mass divided by the square of body height, and may be expressed in units of kg/m 2
  • Body mass (body weight) may be obtained using a scale.
  • Body height may be measured using a ruler or a measuring tape.
  • Body height may include the height of a standing subject.
  • Body height may include a distance from the bottom of a subject’s feet to the top of the subject’s head.
  • BMI may include BMI prime.
  • the subject may have a baseline BMI in a range exemplified in Table 3.
  • the baseline measurement is a baseline waist circumference measurement.
  • a baseline waist circumference measurement may be obtained using a measuring tape.
  • the baseline measurement is a baseline hip circumference measurement.
  • a baseline hip circumference measurement may be obtained using a measuring tape.
  • the baseline measurement is a baseline waist-hip ratio.
  • a baseline waist-hip ratio may be obtained using a measuring tape.
  • the baseline measurement is a baseline body fat percentage.
  • a baseline body fat percentage may be obtained using underwater weighing, whole-body air displacement plethysmography, near-infrared interactance, dual energy X-ray absorptiometry, bioelectrical impedance, or a skinfold test.
  • the baseline measurement is a baseline glucose measurement.
  • the baseline glucose measurement is a baseline glucose concentration (for example, mg/dL).
  • the baseline glucose measurement comprises a baseline glucose concentration.
  • the baseline glucose measurement is a baseline circulating glucose measurement.
  • the baseline glucose measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline glucose measurement is obtained.
  • the baseline glucose measurement comprises a baseline glucose tolerance test.
  • the baseline glucose tolerance test comprises administering glucose to the subject, and then obtaining multiple baseline glucose measurements over time after administering the glucose to the subject.
  • the glucose is administered orally.
  • the glucose is administered by injection.
  • the multiple baseline glucose measurements are integrated into a baseline glucose area under the curve (AUC) measurement.
  • the baseline glucose tolerance test is performed on the subject in a fasted state such as after an overnight fast.
  • the baseline glucose measurement comprises a baseline glucose measurement other than a baseline glucose tolerance test.
  • the baseline measurement is a baseline insulin measurement.
  • the baseline insulin measurement is a baseline insulin sensitivity measurement.
  • the baseline insulin sensitivity measurement is obtained using a glucose clamp technique such as ahyperinsulinemic eugly cemic clamp.
  • the baseline insulin measurement is a baseline insulin concentration.
  • the baseline insulin measurement comprises a baseline insulin concentration.
  • the baseline insulin measurement is a baseline circulating insulin measurement.
  • the baseline insulin measurement is obtained by an assay such as an immunoassay (for example, an ELISA or an immunoblot), a colorimetric assay, or a fluorescence assay.
  • the baseline insulin sensitivity measurement comprises a baseline glucose tolerance test. In some embodiments, the baseline insulin sensitivity measurement comprises a baseline insulin sensitivity measurement other than a baseline glucose tolerance test. [00277] In some embodiments, the baseline insulin measurement comprises a baseline insulin response test. In some embodiments, the baseline insulin response test comprises administering glucose to the subject and then obtaining multiple baseline insulin measurements over time after administering the glucose to the subject. In some embodiments, the glucose is administered orally. In some embodiments, the glucose is administered by injection. In some embodiments, the multiple baseline insulin measurements are integrated into a baseline insulin AUC measurement. In some embodiments, the baseline insulin response test is performed on the subject in a fasted state such as after an overnight fast.
  • the baseline insulin measurement comprises a baseline glucose response test.
  • the baseline glucose response test comprises administering insulin to the subject, and then obtaining multiple baseline glucose measurements over time after administering the insulin to the subject.
  • the insulin is administered by injection.
  • the multiple baseline glucose measurements are integrated into a baseline glucose AUC measurement.
  • the multiple baseline glucose measurements are obtained with a glucometer.
  • the glucose response test is performed on the subject in a fasted state such as after an overnight fast.
  • the glucose response test is performed on the subject after administering food, drink, or glucose to the subject.
  • the baseline measurement is a baseline triglyceride measurement.
  • the baseline triglyceride measurement is a baseline triglyceride concentration (for example, mg/dL). In some embodiments, the baseline triglyceride measurement is a baseline circulating triglyceride measurement. In some embodiments, the baseline triglyceride measurement a baseline circulating triglyceride measurement above 150 mg/dL. In some embodiments, the baseline triglyceride measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline cholesterol measurement.
  • the baseline cholesterol concentration is a baseline total cholesterol measurement.
  • the baseline cholesterol concentration is a baseline non-high density lipoprotein (HDL) cholesterol measurement.
  • the baseline cholesterol concentration is a baseline low density lipoprotein (LDL) cholesterol measurement.
  • the baseline cholesterol measurement is a baseline cholesterol concentration.
  • the baseline cholesterol measurement is a baseline circulating cholesterol measurement.
  • the baseline cholesterol measurement is a baseline blood cholesterol measurement.
  • the baseline cholesterol measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline liver enzyme measurement.
  • the baseline liver enzyme measurement is a baseline alanine aminotransferase (ALT) measurement.
  • the baseline liver enzyme measurement is a baseline aspartate aminotransferase (AST) measurement.
  • the baseline liver enzyme measurement comprises an ALT/ AST ratio, or comprises an AST/ ALT ratio.
  • the baseline liver enzyme measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or HPLC.
  • the baseline measurement is a baseline alanine aminotransferase (ALT) measurement.
  • the baseline ALT measurement is a baseline ALT concentration (for example, Units/dL).
  • the baseline ALT measurement is a baseline circulating ALT measurement, for example, a baseline blood, serum, or plasma ALT measurement.
  • the baseline ALT measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline ALT measurement is within a reference range of 34 IU/L or lower (e.g., for a female subject) or within a reference range of 45 IU/L or lower (e.g., for a male subject). In some embodiments, the baseline ALT measurement is above the reference range.
  • the baseline measurement is a baseline aspartate aminotransferase (AST) measurement.
  • the baseline AST measurement is a baseline AST concentration (for example, Units/L).
  • the baseline AST measurement is a baseline circulating AST measurement, for example, a baseline blood, serum, or plasma AST measurement.
  • the baseline AST measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline AST measurement is within a reference range of 6-34 IU/L (e. g.
  • the baseline AST measurement is above the reference range. In some embodiments, the baseline AST measurement is below the reference range.
  • the baseline measurement is a baseline liver steatosis measurement.
  • the baseline liver steatosis measurement is a baseline liver fat percentage (LFP) measurement.
  • the baseline measurement is a baseline LFP measurement.
  • the baseline LFP measurement is indicated as amass/mass percentage of fat/total tissue.
  • the baseline LFP measurement is indicated as a mass/volume percentage of fat/total tissue.
  • the baseline LFP measurement is indicated as a volume/mass percentage of fat/total tissue.
  • the baseline LFP measurement is indicated as a volume/volume percentage of fat/total tissue.
  • the baseline LFP measurement is indicated as a score. In some embodiments, the baseline LFP measurement is obtained noninvasively. In some embodiments, the baseline LFP measurement is obtained by a medical imaging device. In some embodiments, the baseline LFP measurement is obtained by a device such as a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, a controlled attenuation parameter (CAP), a transient elastography device, or an ultrasound device. In some embodiments, the baseline LFP measurement is obtained in a liver sample. In some embodiments, the baseline LFP measurement comprises a baseline liver triglyceride measurement.
  • MRI medical resonance imaging
  • CAP controlled attenuation parameter
  • the baseline LFP measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline LFP measurement or the baseline LFP measurement is obtained using a scoring system upon a visual inspection of a sample such as a histological sample. In some embodiments, the baseline LFP measurement or the baseline LFP measurement is obtained using a stain with an affinity to fats, such as a lysochrome diazo dye.
  • the baseline measurement is a baseline liver fibrosis measurement.
  • the baseline liver fibrosis measurement is a baseline liver fibrosis score (LFS).
  • the LFS comprises a score of 0, 1, 2, 3, or 4, or a range of scores defined by any two of the aforementioned numbers.
  • the LFS comprises a score of 0-4.
  • the LFS is obtained using a scoring system exemplified in Table 4.
  • the baseline LFS measurement is obtained noninvasively.
  • the baseline LFS measurement is obtained by a medical imaging device such as a vibration-controlled transient elastography (VCTE) device, a shear wave elastography device, a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, or an ultrasound device.
  • a medical imaging device such as a vibration-controlled transient elastography (VCTE) device, a shear wave elastography device, a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, or an ultrasound device.
  • the baseline LFS measurement is obtained in a liver sample.
  • the baseline LFS is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the LFS is obtained using one or more indirect markers or measures of liver fibrosis such as an aspartate aminotransferase-to-platelet ratio index (APRI), aFibrosis- 4 (FIB-4) index, a FibroIndex, a Forns Index, a Hepascore, or a FibroTest.
  • the LFS is obtained using one or more indirect markers or measures of liver fibrosis such as a FIBROSpect test or a FIBROSpect II test.
  • the baseline LFS is obtained by RT-qPCR or RNA sequencing of one or more fibrosis-related genes such as a collagen gene.
  • the baseline LFS or the baseline LFS is obtained using a scoring system upon a visual inspection of a sample such as a histological sample. In some embodiments, the baseline LFS or the baseline LFS is obtained using a stain with an affinity to collagen.
  • the baseline liver fibrosis measurement is a baseline nonalcoholic fatty liver disease (NAFLD) fibrosis score.
  • a baseline NAFLD fibrosis score may take into account laboratory test values such as platelet count, albumin, and AST/ ALT ratio, and patient characteristics such as BMI, and diabetes status.
  • a baseline NAFLD fibrosis score below -1.455 may be indicative of no fibrosis, mild fibrosis, or moderate fibrosis.
  • a baseline NAFLD fibrosis score between -1.455 and 0.675 may be indicative of severe fibrosis.
  • a baseline NAFLD fibrosis score above 0.675 may be indicative of cirrhosis.
  • the baseline measurement is a baseline non-alcoholic fatty liver disease (NAFLD) activity score.
  • the baseline NAFLD activity score comprises a numerical value such as a number of points. In some embodiments, the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a range defined by any two of the aforementioned numerical values. In some embodiments, the numerical value is 0-8.
  • the baseline NAFLD activity score comprises a steatosis grade such as a baseline liver fat percentage. In some embodiments, a steatosis grade ⁇ 5% comprises 0 points in the baseline NAFLD activity score.
  • a steatosis grade of 5- 33% comprises 1 point in the baseline NAFLD activity score. In some embodiments, a steatosis grade of 34-66% comprises 2 points in the baseline NAFLD activity score. In some embodiments, a steatosis grade of > 66% comprises 3 points in the baseline NAFLD activity score. In some embodiments, the baseline NAFLD activity score comprises a lobular inflammation grade. In some embodiments, the lobular inflammation grade comprises an assessment of inflammatory foci. In some embodiments, a lobular inflammation grade comprising 0 foci comprises 0 points in the baseline NAFLD activity score.
  • a lobular inflammation grade comprising 1 focus per a field comprises 1 point in the baseline NAFLD activity score.
  • a lobular inflammation grade comprising 2-4 foci per field comprises 2 points in the baseline NAFLD activity score.
  • a lobular inflammation grade comprising > 4 foci per field comprises 3 points in the baseline NAFLD activity score.
  • the baseline NAFLD activity score comprises a liver cell injury grade such as an amount of ballooning cells.
  • a liver cell injury comprising no ballooning cells comprises 0 points in the baseline NAFLD activity score.
  • a liver cell injury comprising some new balloon cells comprises 1 points in the baseline NAFLD activity score. In some embodiments, a liver cell injury comprising many ballooning cells or prominent ballooning comprises 2 points in the baseline NAFLD activity score. In some embodiments, the baseline NAFLD activity score is obtained invasively, based on histology, and/or in a liver biopsy.
  • the baseline measurement is a baseline gamma-glutamyl transferase (GGT) measurement.
  • the baseline GGT measurement is a baseline GGT concentration.
  • the baseline GGT measurement is a baseline blood GGT measurement.
  • the baseline GGT measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a chromatography assay, or a fluorescence assay.
  • the baseline measurement is a baseline hair count.
  • the baseline hair count is a baseline total hair count.
  • the baseline total hair count may include a baseline vellus hair count and a baseline non-vellus hair count.
  • the baseline hair count is a baseline vellus hair count.
  • the baseline hair count is a baseline non-vellus hair count.
  • the baseline hair count is determined in an area of skin.
  • the baseline hair count is normalized based on the area of skin.
  • the baseline hair count is assessed using photography.
  • the baseline hair count is assessed by phototrichogram.
  • the baseline hair count is assessed by a macrophotography analysis.
  • the baseline measurement is a baseline hair thickness measurement.
  • the baseline hair thickness measurement is determined in an area of skin.
  • the baseline hair thickness measurement comprises a width of an individual hair.
  • the baseline hair thickness measurement comprises widths of multiple individual hairs.
  • the baseline hair thickness measurement comprises an average of the widths of the multiple individual hairs.
  • the baseline hair thickness measurement comprises a median of the widths of the multiple individual hairs.
  • the baseline hair thickness measurement may include a baseline vellus hair thickness measurement.
  • the baseline hair thickness measurement may include a baseline non-vellus hair thickness measurement.
  • the baseline hair thickness measurement is assessed using photography.
  • the baseline hair thickness measurement is assessed by phototrichogram.
  • the baseline hair thickness measurement is assessed by a macrophotography analysis.
  • the baseline measurement is a baseline hair density measurement.
  • the baseline hair density measurement is determined in an area of skin.
  • the baseline hair density measurement comprises a number of hair in the area of skin.
  • the baseline hair density measurement comprises the number of hair in the area of skin divided by the area of skin.
  • the baseline hair density measurement may include a baseline vellus hair density measurement.
  • the baseline hair density measurement may include a baseline non-vellus hair density measurement.
  • the baseline hair density measurement is assessed using photography.
  • the baseline hair density measurement is assessed by phototrichogram.
  • the baseline hair density measurement is assessed by a macrophotography analysis.
  • the baseline measurement is a baseline S0S2 protein measurement.
  • the baseline S0S2 protein measurement comprises a baseline S0S2 protein level.
  • the baseline S0S2 protein level is indicated as amass or percentage of S0S2 protein per sample weight.
  • the baseline S0S2 protein level is indicated as a mass or percentage of S0S2 protein per sample volume.
  • the baseline S0S2 protein level is indicated as a mass or percentage of S0S2 protein per total protein within the sample.
  • the baseline S0S2 protein measurement is a baseline tissue S0S2 protein measurement.
  • baseline tissue S0S2 protein measurements include a baseline liver S0S2 protein measurement, a baseline kidney S0S2 protein measurement, a baseline eye S0S2 protein measurement, or a baseline adipose tissue S0S2 protein measurement.
  • the baseline S0S2 protein measurement is a baseline circulating S0S2 protein measurement.
  • the baseline S0S2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline measurement is a baseline S0S2 mRNA measurement.
  • the baseline S0S2 mRNA measurement comprises a baseline S0S2 mRNA level.
  • the baseline S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per sample weight.
  • the baseline S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per sample volume.
  • the baseline S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per total mRNA within the sample.
  • the baseline S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per total nucleic acids within the sample. In some embodiments, the baseline S0S2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline S0S2 mRNA measurement is a baseline tissue S0S2 mRNA measurement. Examples of baseline tissue S0S2 mRNA measurements include a baseline liver S0S2 mRNA measurement, a baseline kidney S0S2 mRNA measurement, a baseline eye S0S2 mRNA measurement, or a baseline adipose tissue S0S2 mRNA measurement.
  • the baseline S0S2 mRNA measurement is a baseline circulating S0S2 mRNA measurement.
  • the baseline S0S2 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 S0S2 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 is obtained from the subject in a fasted state.
  • the sample is obtained from the subject after an overnight fasting period.
  • the sample is obtained from the subject in a fed state.
  • the sample comprises a fluid.
  • the sample is a fluid sample.
  • the sample is a blood, plasma, or serum sample.
  • the sample comprises blood.
  • the sample is a blood sample.
  • the sample is a whole-blood sample.
  • the blood is fractionated or centrifuged.
  • the sample comprises plasma.
  • the sample is a plasma sample.
  • the sample comprises serum.
  • the sample is a serum sample.
  • the sample comprises a tissue.
  • the sample is a tissue sample.
  • the sample comprises liver tissue.
  • the sample is a liver sample.
  • the sample comprises adipose tissue.
  • the sample is an adipose sample.
  • the tissue sample comprises brown adipose tissue or white adipose tissue.
  • the sample comprises kidney tissue.
  • the sample is a kidney sample.
  • the sample comprises eye tissue.
  • the sample is an eye sample.
  • the sample comprises an eye fluid.
  • the sample comprises a hair or scalp sample.
  • the baseline S0S2 mRNA measurement, or the baseline S0S2 protein measurement may be obtained in a liver, adipose, eye, or kidney sample from the patient.
  • the sample comprises cardiac tissue such as ventricular or atrial tissue.
  • the sample comprises a cerebral tissue or fluid.
  • the sample comprises a neural tissue or neural fluid.
  • the sample comprises a muscle tissue or fluid.
  • the sample may comprise or consist of hepatocytes.
  • the sample may comprise or consist of podocytes.
  • the composition or administration of the composition affects a measurement such as include a glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGFR) measurement, a creatinine measurement, a blood urea nitrogen (BUN) measurement, a proteinuria measurement, a microalbuminuria measurement, a blood urate measurement, a urine albumin creatine ratio, a systolic blood pressure (SBP) measurement, a diastolic blood pressure (DBP) measurement, a mean arterial pressure measurement, a pulse pressure measurement, a intraocular pressure (IOP) measurement, a cup-disc ratio, a RNFL thickness measurement, a optic nerve head cupping measurement, a RPE pigmentation and reflectivity measurement, a retinal thickness measurement, a drusen measurement, a macular hemorrhage measurement, a choroidal neovascularization measurement, a edema measurement, a microaneurysm measurement, a
  • GFR glomerular filtration
  • Some embodiments of the methods described herein include obtaining the measurement from a subject.
  • the measurement may be obtained from the subject after treating the subject.
  • the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject.
  • the measurement is an indication that the disorder has been treated.
  • the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, or a PCR assay.
  • the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence 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.
  • the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition.
  • the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition.
  • 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.
  • 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.
  • the reduction is measured in a second tissue sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, 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.
  • 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 95% 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 95%, or by a range defined by any of the two aforementioned percentages.
  • the composition increases the measurement relative to the baseline measurement.
  • the increase is measured in a second tissue 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.
  • the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than 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.
  • the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a GFR or eGFR measurement. In some embodiments, the measurement is a GFR measurement. In some embodiments, the measurement is a eGFR measurement.
  • the GFR or eGFR measurement may be indicated in units of volume per time (e.g. , mL/min).
  • the GFR measurement may be obtained using a clearance measurement such as a creatinine clearance measurement.
  • the GFR may also be determined by injecting insulin, sinistrin, a radioactive tracer, or cystatin C, and determining a clearance rate.
  • the eGFR measurement may be also be obtained using a clearance estimate such as an estimation of serum creatinine clearance.
  • the GFR or eGFR may be 100-130 mL/min/1.73m 2 , 90-100 mL/min/1.73m 2 .
  • the GFR or eGFR may be below 90 or 100 mL/min/1.73m 2 .
  • the GFR or eGFR may be indicative of normal kidney function, CKD1, CKD2, CKD3, CKD4, or CKD5, as indicated by a kidney function index.
  • the composition increases the GFR measurement relative to the baseline GFR or eGFR measurement. In some embodiments, the composition increases the eGFR measurement relative to the baseline GFR or eGFR measurement. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the GFR or eGFR measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline GFR or eGFR measurement. In some embodiments, the GFR or eGFR measurement is increased by about 10% or more, relative to the baseline GFR or eGFR measurement.
  • the GFR or eGFR 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 GFR or eGFR measurement. In some embodiments, the GFR or eGFR 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 GFR or eGFR measurement. In some embodiments, the GFR or eGFR 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 GFR or eGFR measurement.
  • the GFR or eGFR measurement is increased by no more than about 10%, relative to the baseline GFR or eGFR measurement. In some embodiments, the GFR or eGFR 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 GFR or eGFR measurement.
  • the GFR or eGFR 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 GFR or eGFR measurement. In some embodiments, the GFR or eGFR measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a creatinine measurement.
  • the creatinine measurement is a creatinine concentration.
  • the creatinine measurement is a circulating (e.g., serum or plasma) creatinine measurement.
  • the creatinine measurement is a urine creatinine measurement.
  • the creatinine measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the circulating creatinine measurement may be about 0.5-1.3 mg/dL.
  • the circulating creatinine measurement may be above 1.3 mg/dL.
  • the circulating creatinine measurement may be within, above, or below a reference range.
  • the urine creatinine measurement may be within, above, or below a reference range.
  • the composition reduces the creatinine measurement relative to the baseline creatinine measurement.
  • the reduction is measured in a second fluid 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 creatinine measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline creatinine measurement.
  • the creatinine measurement is decreased by about 10% or more, relative to the baseline creatinine measurement.
  • the creatinine 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 creatinine measurement. In some embodiments, the creatinine 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 creatinine measurement. In some embodiments, the creatinine measurement is decreased by no more than about 10%, relative to the baseline creatinine measurement.
  • the creatinine 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%, or no more than about 90%relative to the baseline creatinine measurement. In some embodiments, the creatinine measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a blood urea nitrogen (BUN) measurement.
  • the BUN measurement is a BUN concentration.
  • the BUN measurement is a circulating BUN measurement.
  • the BUN measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the BUN is 6-20 mg/dL.
  • the BUN is over 20 mg/dL.
  • a normal BUN range is 6-20 mg/dL.
  • the measurement is a BUN/creatinine ratio.
  • the composition reduces the BUN measurement relative to the baseline BUN measurement.
  • the reduction is measured in a second blood sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the BUN measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline BUN measurement. In some embodiments, the BUN measurement is decreased by about 10% or more, relative to the baseline BUN measurement. In some embodiments, the BUN 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 BUN measurement.
  • the BUN 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 BUN measurement. In some embodiments, the BUN measurement is decreased by no more than about 10%, relative to the baseline BUN measurement. In some embodiments, the BUN 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%, or no more than about 90%relative to the baseline BUN measurement. In some embodiments, the BUN measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a proteinuria measurement.
  • the proteinuria measurement may be indicated as a concentration, a ratio, or a mass/unit time (e.g., mg/mmol urine, protein/creatinine, or mg protein/hr).
  • the proteinuria measurement includes a proteinuria concentration.
  • the proteinuria measurement is a urine proteinuria measurement.
  • the proteinuria measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the proteinuria measurement is indicative of proteinuria in the subject.
  • the proteinuria measurement is indicative of a lack of proteinuria in the subj ect.
  • the measurement is a urine protein/creatinine ratio.
  • the composition reduces the proteinuria measurement relative to the baseline proteinuria measurement.
  • the reduction is measured in a second fluid 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 proteinuria measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline proteinuria measurement.
  • the proteinuria measurement is decreased by about 10% or more, relative to the baseline proteinuria measurement.
  • the proteinuria 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 proteinuria measurement. In some embodiments, the proteinuria 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 proteinuria measurement. In some embodiments, the proteinuria measurement is decreased by no more than about 10%, relative to the baseline proteinuria measurement.
  • the proteinuria 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%, or no more than about 90% relative to the baseline proteinuria measurement. In some embodiments, the proteinuria measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a microalbuminuria measurement.
  • the microalbuminuria measurement may be indicated as a concentration, a ratio, or a mass/unit time (e.g., mg/mmol urine, albumin/creatinine, or mg albumin/hr).
  • the microalbuminuria measurement includes a microalbuminuria concentration.
  • the microalbuminuria measurement is a urine microalbuminuria measurement.
  • the microalbuminuria measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the microalbuminuria measurement is indicative of microalbuminuria in the subject.
  • the microalbuminuria measurement is indicative of a lack of microalbuminuria in the subject.
  • the measurement is a urine albumin/creatinine ratio.
  • the microalbuminuria measurement may include a microalbuminuria measurement within a range or amount defined in Table 2.
  • the composition reduces the microalbuminuria measurement relative to the baseline microalbuminuria measurement.
  • the reduction is measured in a second fluid 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 microalbuminuria measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline microalbuminuria measurement.
  • the microalbuminuria measurement is decreased by about 10% or more, relative to the baseline microalbuminuria measurement.
  • the microalbuminuria 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 microalbuminuria measurement. In some embodiments, the microalbuminuria 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 microalbuminuria measurement. In some embodiments, the microalbuminuria measurement is decreased by no more than about 10%, relative to the baseline microalbuminuria measurement.
  • the microalbuminuria 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%, or no more than about 90%relative to the baseline microalbuminuria measurement. In some embodiments, the microalbuminuria measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a blood urate measurement.
  • the blood urate measurement is a blood urate concentration.
  • the blood urate measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the blood urate measurement is indicative of hyperuricemia.
  • the blood urate measurement is indicative of a lack of hyperuricemia.
  • the serum uric acid measurement may be 6 mg/dL or less, 7 mg/dL or less, or 5.5 mg/dL or less.
  • the composition reduces the blood urate measurement relative to the baseline blood urate measurement.
  • the reduction is measured in a second blood 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 blood urate measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline blood urate measurement.
  • the blood urate measurement is decreased by about 10% or more, relative to the baseline blood urate measurement.
  • the blood urate 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 blood urate measurement. In some embodiments, the blood urate 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 blood urate measurement. In some embodiments, the blood urate measurement is decreased by no more than about 10%, relative to the baseline blood urate measurement.
  • the blood urate 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%, or no more than about 90%relative to the baseline blood urate measurement. In some embodiments, the blood urate measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a systolic blood (SBP) pressure measurement.
  • the SBP measurement is measured in mm of mercury (mm Hg).
  • the SBP measurement is obtained with a sphygmomanometer.
  • the SBP measurement may be indicative of hypertension.
  • the SBP measurement may be indicative of normal blood pressure.
  • the SBP measurement may include a cerebral SBP measurement.
  • the composition reduces the SBP measurement relative to the baseline SBP measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the SBP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline SBP measurement. In some embodiments, the SBP measurement is decreased by about 10% or more, relative to the baseline SBP measurement. In some embodiments, the SBP 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 SBP measurement.
  • the SBP 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 SBP measurement. In some embodiments, the SBP measurement is decreased by no more than about 10%, relative to the baseline SBP measurement. In some embodiments, the SBP 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%, or no more than about 90%relative to the baseline SBP measurement. In some embodiments, the SBP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a diastolic blood (DBP) pressure measurement.
  • the DBP measurement is measured in mm of mercury (mm Hg).
  • the DBP measurement is obtained with a sphygmomanometer.
  • the DBP measurement may be indicative of hypertension.
  • the DBP measurement may be indicative of normal blood pressure.
  • the DBP measurement may include a cerebral DBP measurement.
  • the composition reduces the DBP measurement relative to the baseline DBP measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the DBP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline DBP measurement. In some embodiments, the DBP measurement is decreased by about 10% or more, relative to the baseline DBP measurement. In some embodiments, the DBP 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 DBP measurement.
  • the DBP 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 DBP measurement. In some embodiments, the DBP measurement is decreased by no more than about 10%, relative to the baseline DBP measurement. In some embodiments, the DBP 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%, or no more than about 90%relative to the baseline DBP measurement. In some embodiments, the DBP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a mean arterial pressure (MAP) pressure measurement.
  • the MAP measurement is measured in mm of mercury (mm Hg).
  • the MAP measurement is obtained with a sphygmomanometer.
  • the MAP measurement may be indicative of hypertension.
  • the MAP measurement may be indicative of normal blood pressure.
  • the MAP measurement may include a cerebral MAP measurement.
  • the composition reduces the MAP measurement relative to the baseline MAP measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the MAP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MAP measurement.
  • the MAP measurement is decreased by about 10% or more, relative to the baseline MAP measurement. In some embodiments, the MAP 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 MAP measurement. In some embodiments, the MAP 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 MAP measurement. In some embodiments, the MAP measurement is decreased by no more than about 10%, relative to the baseline MAP measurement.
  • the MAP 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%, or no more than about 90%relative to the baseline MAP measurement. In some embodiments, the MAP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a pulse pressure measurement.
  • the pulse pressure measurement is measured in mm of mercury (mm Hg).
  • the pulse pressure measurement is obtained with a sphygmomanometer.
  • the pulse pressure measurement may be indicative of hypertension.
  • the pulse pressure measurement may be indicative of normal blood pressure.
  • the pulse pressure measurement may include a cerebral pulse pressure measurement.
  • the composition reduces the pulse pressure measurement relative to the baseline pulse pressure measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the pulse pressure measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline pulse pressure measurement. In some embodiments, the pulse pressure measurement is decreased by about 10% or more, relative to the baseline pulse pressure measurement. In some embodiments, the pulse pressure 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 pulse pressure measurement.
  • the pulse pressure 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 pulse pressure measurement. In some embodiments, the pulse pressure measurement is decreased by no more than about 10%, relative to the baseline pulse pressure measurement. In some embodiments, the pulse pressure 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%, or no more than about 90%relative to the baseline pulse pressure measurement. In some embodiments, the pulse pressure measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a intraocular pressure (IOP) measurement.
  • the IOP may be measured using a tonometer.
  • the IOP measurement may be in millimeters of mercury (mmHg).
  • the IOP measurement may be indicative of a normal IOP.
  • the IOP measurement may be indicative of abnormal or high IOP.
  • the composition reduces the IOP measurement relative to the baseline IOP measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the IOP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline IOP measurement. In some embodiments, the IOP measurement is decreased by about 10% or more, relative to the baseline IOP measurement. In some embodiments, the IOP 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 IOP measurement.
  • the IOP 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 IOP measurement. In some embodiments, the IOP measurement is decreased by no more than about 10%, relative to the baseline IOP measurement. In some embodiments, the IOP 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%, or no more than about 90%relative to the baseline IOP measurement. In some embodiments, the IOP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a measurement of optic nerve head cupping.
  • the measurement of optic nerve head cupping may be a cup-disc ratio measurement.
  • the cup-disc ratio may be measured using a slit lamp.
  • the cup-disc ratio measurement may be indicative of a normal cup-disc ratio.
  • the cup-disc ratio measurement may be indicative of a high or abnormal cup-disc ratio.
  • the composition reduces the cup-disc ratio measurement relative to the baseline cup-disc ratio measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the cup-disc ratio measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline cup-disc ratio measurement. In some embodiments, the cup-disc ratio measurement is decreased by about 10% or more, relative to the baseline cup-disc ratio measurement. In some embodiments, the cup-disc ratio 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 cup-disc ratio measurement.
  • the cupdisc ratio 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 cup-disc ratio measurement. In some embodiments, the cup-disc ratio measurement is decreased by no more than about 10%, relative to the baseline cup-disc ratio measurement. In some embodiments, the cup-disc ratio 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%, or no more than about 90%relative to the baseline cup-disc ratio measurement. In some embodiments, the cup-disc ratio measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a retinal nerve fiber layer (RNFL) thickness measurement.
  • the RNFL thickness may be measured using optical coherence tomography.
  • the RNFL thickness measurement may be in pm.
  • the RNFL thickness measurement may be indicative of a normal RNFL thickness measurement.
  • the RNFL thickness measurement may be indicative of a low or abnormal RNFL thickness measurement.
  • the composition increases the RNFL thickness measurement relative to the baseline RNFL thickness measurement. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the RNFL thickness measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline RNFL thickness measurement. In some embodiments, the RNFL thickness measurement is increased by about 10% or more, relative to the baseline RNFL thickness measurement. In some embodiments, the RNFL thickness 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 RNFL thickness measurement.
  • the RNFL thickness 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 RNFL thickness measurement. In some embodiments, the RNFL thickness measurement is increased by no more than about 10%, relative to the baseline RNFL thickness measurement. In some embodiments, the RNFL thickness 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%, or no more than about 90%relative to the baseline RNFL thickness measurement. In some embodiments, the RNFL thickness measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a retinal thickness measurement.
  • the retinal thickness may be measured using optical coherence tomography.
  • the retinal thickness measurement may be in pm.
  • the retinal thickness measurement may be indicative of a normal retinal thickness measurement.
  • the retinal thickness measurement may be indicative of a high or abnormal retinal thickness measurement.
  • the composition reduces the retinal thickness measurement relative to the baseline retinal thickness measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the retinal thickness measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline retinal thickness measurement. In some embodiments, the retinal thickness measurement is decreased by about 10% or more, relative to the baseline retinal thickness measurement. In some embodiments, the retinal thickness 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 retinal thickness measurement.
  • the retinal thickness 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 retinal thickness measurement. In some embodiments, the retinal thickness measurement is decreased by no more than about 10%, relative to the baseline retinal thickness measurement. In some embodiments, the retinal thickness 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%, or no more than about 90%relative to the baseline retinal thickness measurement. In some embodiments, the retinal thickness measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a edema measurement.
  • the edema may be measured using optical coherence tomography.
  • the edema measurement may be in pm. .
  • the edema measurement may be indicative of a normal edema measurement.
  • the edema measurement may be indicative of a high or abnormal edema measurement.
  • the composition reduces the edema measurement relative to the baseline edema measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the edema measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline edema measurement. In some embodiments, the edema measurement is decreased by about 10% or more, relative to the baseline edema measurement. In some embodiments, the edema 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 edema measurement.
  • the edema 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 edema measurement. In some embodiments, the edema measurement is decreased by no more than about 10%, relative to the baseline edema measurement. In some embodiments, the edema 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%, or no more than about 90%relative to the baseline edema measurement. In some embodiments, the edema measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity measurement may be measured using optical coherence tomography.
  • the RPE pigmentation and reflectivity measurement may be indicative of a normal RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity measurement may be indicative of abnormal RPE pigmentation and reflectivity.
  • the composition reduces the RPE pigmentation and reflectivity measurement relative to the baseline RPE pigmentation and reflectivity measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the RPE pigmentation and reflectivity measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline RPE pigmentation and reflectivity measurement. In some embodiments, the RPE pigmentation and reflectivity measurement is decreased by about 10% or more, relative to the baseline RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity 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 RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity measuremait 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 RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity measurement is decreased by no more than about 10%, relative to the baseline RPE pigmentation and reflectivity measurement.
  • the RPE pigmentation and reflectivity 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%, or no more than about 90%relative to the baseline RPE pigmentation and reflectivity measurement. In some embodiments, the RPE pigmentation and reflectivity measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a drusen measurement.
  • the drusen may be measured using an eye exam or retinal photography.
  • the drusen measurement may be the size of the drusen or the number of the drusen.
  • the drusen measurement may be indicative of a normal drusen measurement.
  • the drusen measurement may be indicative of a high or abnormal drusen measurement.
  • the composition reduces the drusen measurement relative to the baseline drusen measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject.
  • the drusen measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline drusen measurement. In some embodiments, the drusen measurement is decreased by about 10% or more, relative to the baseline drusen measurement. In some embodiments, the drusen 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 drusai measurement. In some embodiments, the drusen 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 drusen measurement.
  • the drusen measurement is decreased by no more than about 10%, relative to the baseline drusen measurement. In some embodiments, the drusen 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%, or no more than about 90%relative to the baseline drusen measurement. In some embodiments, the drusen measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a hemorrhage measurement.
  • the hemorrhage measurement may be a vitreous hemorrhage.
  • the hemorrhage measurement may be an intraretinal hemorrhage.
  • the hemorrhage may be a macular hemorrhage.
  • the hemorrhage may be measured using retinal photography.
  • the hemorrhage measurement may be indicative of a normal hemorrhage measurement.
  • the hemorrhage measurement may be indicative of an abnormal or high hemorrhage measurement.
  • the composition reduces the hemorrhage measurement relative to the baseline hemorrhage measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the hemorrhage measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hemorrhage measurement. In some embodiments, the hemorrhage measurement is decreased by about 10% or more, relative to the baseline hemorrhage measurement.
  • the hemorrhage 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 hemorrhage measurement. In some embodiments, the hemorrhage 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 hemorrhage measurement. In some embodiments, the hemorrhage measurement is decreased by no more than about 10%, relative to the baseline hemorrhage measurement.
  • the hemorrhage 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%, or no more than about 90%relative to the baseline hemorrhage measurement. In some embodiments, the hemorrhage measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a macular ischemia measurement.
  • the macular ischemia may be measured using fluorescein angiography or optical coherence tomography angiography.
  • the macular ischemia measurement may be a measurement of the foveal avascular zone.
  • the macular ischemia measurement may be indicative of a normal macular ischemia measurement.
  • the macular ischemia measurement may be indicative of a high or abnormal macular ischemia measurement.
  • the composition reduces the macular ischemia measurement relative to the baseline macular ischemia measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the macular ischemi a measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline macular ischemia measurement. In some embodiments, the macular ischemia measurement is decreased by about 10% or more, relative to the baseline macular ischemia measurement.
  • the macular ischemia 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 macular ischemia measurement. In some embodiments, the macular ischemia 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 macular ischemia measurement. In some embodiments, the macular ischemia measurement is decreased by no more than about 10%, relative to the baseline macular ischemia measurement.
  • the macular ischemia 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%, or no more than about 90%relative to the baseline macular ischemia measurement. In some embodiments, the macular ischemia measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a microaneurysm measurement.
  • the microaneurysm may be measured using fluorescein angiography.
  • the microaneurysm measurement may be the count of microaneurysms.
  • the microaneurysm measurement may be indicative of a normal microaneurysm measurement.
  • the microaneurysm measurement may be indicative of high or abnormal microaneurysm measurement.
  • the composition reduces the microaneurysm measurement relative to the baseline microaneurysm measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the microaneurysm measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline microaneurysm measurement. In some embodiments, the microaneurysm measurement is decreased by about 10% or more, relative to the baseline microaneurysm measurement.
  • the microaneurysm 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 microaneurysm measurement. In some embodiments, the microaneurysm 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 microaneurysm measurement. In some embodiments, the microaneurysm measurement is decreased by no more than about 10%, relative to the baseline microaneurysm measurement.
  • the microaneurysm 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%, or no more than about 90%relative to the baseline microaneurysm measurement. In some embodiments, the microaneurysm measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a neovascularization measurement.
  • the neovascularization measurement may be a choroidal neovascularization measurement.
  • the neovascularization measurement may be measured using imaging techniques such as fluorescein angiography.
  • the neovascularization measurement may be an area of the neovascularization.
  • the neovascularization measurement may be indicative of a normal neovascularization measurement.
  • the neovascularization measurement may be indicative of a high or abnormal neovascularization measurement.
  • the composition reduces the neovascularization measurement relative to the baseline neovascularization measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the neovascularization measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline neovascularization measurement. In some embodiments, the neovascularization measurement is decreased by about 10% or more, relative to the baseline neovascularization measurement.
  • the neovascularization 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 neovascularization measurement. In some embodiments, the neovascularization 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 neovascularization measurement. In some embodiments, the neovascularization measurement is decreased by no more than about 10%, relative to the baseline neovascularization measurement.
  • the neovascularization 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%, or no more than about 90%relative to the baseline neovascularization measurement. In some embodiments, the neovascularization measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a traction retinal detachment measurement.
  • the traction retinal detachment may be measured using imaging techniques, including optical coherence tomography.
  • the traction retinal detachment measurement may be indicative of a normal retina.
  • the traction retinal detachment measurement may be indicative of macular degeneration or diabetic retinopathy.
  • the composition reduces the traction retinal detachment measurement relative to the baseline traction retinal detachment measurement. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the traction retinal detachment measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline traction retinal detachment measurement. In some embodiments, the traction retinal detachment measurement is decreased by about 10% or more, relative to the baseline traction retinal detachment measurement.
  • the traction retinal detachment 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 traction retinal detachment measurement. In some embodiments, the traction retinal detachment 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 traction retinal detachment measurement. In some embodiments, the traction retinal detachment measurement is decreased by no more than about 10%, relative to the baseline traction retinal detachment measurement.
  • the traction retinal detachment 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%, or no more than about 90%relative to the baseline traction retinal detachment measurement. In some embodiments, the traction retinal detachment measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a hemoglobin A1C measurement.
  • the hemoglobin A1C measurement is a hemoglobin A1C concentration.
  • the hemoglobin A1C measurement is a circulating hemoglobin A1C measurement.
  • the hemoglobin A1C measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or HPLC.
  • the hemoglobin A1C measurement may be indicative of a healthy normal A1C measurement.
  • the hemoglobin A1C measurement may be indicative of diabetes.
  • the hemoglobin A1C measurement may be indicative of pre-diabetes.
  • the composition reduces the hemoglobin A1C measurement relative to the baseline hemoglobin A1C measurement.
  • the reduction is measured in a second fluid 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 hemoglobin A1C measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hemoglobin A1C measurement.
  • the hemoglobin A1C measurement is decreased by about 10% or more, relative to the baseline hemoglobin A1C measurement.
  • the hemoglobin A1C 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 hemoglobin A1C measurement. In some embodiments, the hemoglobin A1C 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 hemoglobin A1C measurement. In some embodiments, the hemoglobin A1C measurement is decreased by no more than about 10%, relative to the baseline hemoglobin A1C measurement.
  • the hemoglobin A1C 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%, or no more than about 90%relative to the baseline hemoglobin A1C measurement. In some embodiments, the hemoglobin A1C measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a body mass measurement.
  • the body mass measurement is a body mass index (BMI).
  • BMI may be defined as a body mass divided by the square of body height, and may be expressed in units of kg/m 2
  • Body mass may be obtained using a scale.
  • Body height may be measured using a ruler or a measuring tape.
  • Body height may include the height of a standing subject.
  • Body height may include a distance from the bottom of a subject’s feet to the top of the subject’s head.
  • BMI may include BMI prime.
  • the subject may have a BMI in a range exemplified in Table 3.
  • the composition reduces the body mass measurement relative to the baseline body mass measurement. In some embodiments, the reduction is measured on the subject after administering the composition to the subject. In some embodiments, the body mass measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline body mass measurement. In some embodiments, the body mass measurement is decreased by about 10% or more, relative to the baseline body mass measurement. In some embodiments, the body mass 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 body mass measurement.
  • the body mass 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 body mass measurement. In some embodiments, the body mass measurement is decreased by no more than about 10%, relative to the baseline body mass measurement. In some embodiments, the body mass 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%, or no more than about 90% relative to the baseline body mass measurement. In some embodiments, the body mass measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a waist circumference measurement.
  • a waist circumference measurement may be obtained using a measuring tape.
  • the composition reduces the waist circumference measurement relative to the baseline waist circumference measurement. In some embodiments, the reduction is measured on the subject after administering the composition to the subject. In some embodiments, the waist circumference measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline waist circumference measurement. In some embodiments, the waist circumference measurement is decreased by about 10% or more, relative to the baseline waist circumference measurement. In some embodiments, the waist circumference 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 waist circumference measurement.
  • the waist circumference 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 waist circumference measurement. In some embodiments, the waist circumference measurement is decreased by no more than about 10%, relative to the baseline waist circumference measurement. In some embodiments, the waist circumference 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%, or no more than about 90% relative to the baseline waist circumference measurement. In some embodiments, the waist circumference measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a hip circumference measurement.
  • a hip circumference measurement may be obtained using a measuring tape.
  • the composition reduces the hip circumference measurement relative to the baseline hip circumference measurement. In some embodiments, the reduction is measured on the subject after administering the composition to the subject. In some embodiments, the hip circumference measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hip circumference measurement. In some embodiments, the hip circumference measurement is decreased by about 10% or more, relative to the baseline hip circumference measurement. In some embodiments, the hip circumference 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 hip circumference measurement.
  • the hip circumference 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 hip circumference measurement. In some embodiments, the hip circumference measurement is decreased by no more than about 10%, relative to the baseline hip circumference measurement. In some embodiments, the hip circumference 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%, or no more than about 90% relative to the baseline hip circumference measurement. In some embodiments, the hip circumference measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a waist-hip ratio.
  • a waist-hip ratio may be obtained using a measuring tape.
  • the composition reduces the waist-hip ratio measurement relative to the baseline waist-hip ratio measurement. In some embodiments, the reduction is measured on the subject after administering the composition to the subject. In some embodiments, the waist-hip ratio measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline waist-hip ratio measurement. In some embodiments, the waist-hip ratio measurement is decreased by about 10% or more, relative to the baseline waist-hip ratio measurement. In some embodiments, the waist-hip ratio 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, or about 80% or more, relative to the baseline waist-hip ratio measurement.
  • the waist-hip ratio 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 waist-hip ratio measurement. In some embodiments, the waist -hip ratio measurement is decreased by no more than about 10%, relative to the baseline waist-hip ratio measurement. In some embodiments, the waist-hip ratio 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%, or no more than about 80%, relative to the baseline waist-hip ratio measurement. In some embodiments, the waist-hip ratio measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or by arange defined by any of the two aforementioned percentages.
  • the measurement is a body fat percentage.
  • a body fat percentage may be obtained using underwater weighing, whole-body air displacement plethysmography, near-infrared interactance, dual energy X-ray absorptiometry, bioelectrical impedance, or a skinfold test.
  • the composition reduces the body fat percentage measurement relative to the baseline body fat percentage measurement. In some embodiments, the reduction is measured on the subject after administering the composition to the subject. In some embodiments, the body fat percentage measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline body fat percentage measurement. In some embodiments, the body fat percentage measurement is decreased by about 10% or more, relative to the baseline body fat percentage measurement. In some embodiments, the body fat percentage 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 body fat percentage measurement.
  • the body fat percentage 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 body fat percentage measurement. In some embodiments, the body fat percentage measurement is decreased by no more than about 10%, relative to the baseline body fat percentage measurement. In some embodiments, the body fat percentage 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%, or no more than about 90% relative to the baseline body fat percentage measurement. In some embodiments, the body fat percentage measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a triglyceride measurement.
  • the triglyceride measurement is a triglyceride concentration (for example, mg/dL).
  • the triglyceride measurement is a circulating triglyceride measurement.
  • the triglyceride measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the composition reduces the triglyceride measurement relative to the baseline triglyceride measurement. In some embodiments, the composition reduces circulating triglycerides relative to the baseline triglyceride measurement. In some embodiments, the reduced triglycerides are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the triglyceride measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline triglyceride measurement. In some embodiments, the triglyceride measurement is decreased by about 10% or more, relative to the baseline triglyceride measurement.
  • the triglyceride 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, or about 100%, relative to the baseline triglyceride measurement. In some embodiments, the triglyceride 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 triglyceride measurement. In some embodiments, the triglyceride measurement is decreased by no more than about 10%, relative to the baseline triglyceride measurement.
  • the triglyceride 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 triglyceride measurement. In some embodiments, the triglyceride measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a cholesterol measurement.
  • the cholesterol concentration is a total cholesterol measurement.
  • the cholesterol concentration is a non -high density lipoprotein (HDL) cholesterol measurement.
  • the cholesterol concentration is a low density lipoprotein (LDL) cholesterol measurement.
  • the cholesterol measurement is a cholesterol concentration.
  • the cholesterol measurement is a circulating cholesterol measurement.
  • the cholesterol measurement is a blood cholesterol measurement.
  • the cholesterol measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the composition reduces the cholesterol measurement relative to the baseline cholesterol measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the cholesterol measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline cholesterol measurement. In some embodiments, the cholesterol measurement is decreased by about 10% or more, relative to the baseline cholesterol measurement. In some embodiments, the cholesterol 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 cholesterol measurement.
  • the cholesterol 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 cholesterol measurement. In some embodiments, the cholesterol measurement is decreased by no more than about 10%, relative to the baseline cholesterol measurement. In some embodiments, the cholesterol 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%, or no more than about 90%, relative to the baseline cholesterol measurement. In some embodiments, the cholesterol measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a liver enzyme measurement.
  • the liver enzyme measurement is an alanine aminotransferase (ALT) measurement.
  • the liver enzyme measurement is an aspartate aminotransferase (AST) measurement.
  • the liver enzyme measurement comprises an ALT/AST ratio, or comprises an AST/ ALT ratio.
  • the measurement is a alanine aminotransferase (ALT) measurement.
  • the ALT measurement is a ALT concentration (for example, Units/dL).
  • the ALT measurement is a circulating ALT measurement, for example, a blood, serum, or plasma ALT measurement.
  • the ALT measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the ALT measurement is within a reference range. In some embodiments, the ALT measurement is above the reference range.
  • the composition reduces the ALT measurement relative to the baseline ALT measurement.
  • the reduced ALT is measured in a second blood sample, plasma sample, or serum sample obtained from the subject after administering the composition to the subject.
  • the ALT measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline ALT measurement.
  • the ALT measurement is decreased by about 10% or more, relative to the baseline ALT measurement.
  • the ALT 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 ALT measurement.
  • the ALT 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 ALT measurement. In some embodiments, the ALT measurement is decreased by no more than about 10%, relative to the baseline ALT measurement. In some embodiments, the ALT 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%, or no more than about 90% relative to the baseline ALT measurement. In some embodiments, the ALT measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a aspartate aminotransferase (AST) measurement.
  • the AST measurement is a AST concentration (for example, Units/L).
  • the AST measurement is a circulating AST measurement, for example, a blood, serum, or plasma AST measurement.
  • the AST measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the AST measurement is within a reference range. In some embodiments, the AST measurement is above the reference range. In some embodiments, the AST measurement is below the reference range.
  • the composition reduces the AST measurement relative to the baseline AST measurement.
  • the reduced AST is measured in a second blood sample, plasma sample, or serum sample obtained from the subject after administering the composition to the subject.
  • the AST measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline AST measurement.
  • the AST measurement is decreased by about 10% or more, relative to the baseline AST measurement.
  • the AST 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 AST measurement.
  • the AST 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 AST measurement. In some embodiments, the AST measurement is decreased by no more than about 10%, relative to the baseline AST measurement. In some embodiments, the AST 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%relative to the baseline AST measurement. In some embodiments, the AST measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a liver steatosis measurement.
  • the liver steatosis measurement is a liver fat percentage (LFP) measurement.
  • the measurement is a LFP measurement.
  • the LFP measurement is indicated as a mass/mass percentage of fat/total tissue.
  • the LFP measurement is indicated as amass/volume percentage of fat/total tissue.
  • the LFP measurement is indicated as a volume/mass percentage of fat/total tissue.
  • the LFP measurement is indicated as a volume/ volume percentage of fat/total tissue.
  • the LFP measurement is indicated as a score.
  • the LFP measurement is obtained noninvasively. In some embodiments, the LFP measurement is obtained by a medical imaging device. In some embodiments, the LFP measurement is obtained by a device such as a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, a controlled attenuation parameter (CAP), a transient elastography device, or an ultrasound device. In some embodiments, the LFP measurement is obtained in a second liver sample. In some embodiments, the LFP measurement comprises a liver triglyceride measurement. In some embodiments, the LFP measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • MRI medical resonance imaging
  • CAP controlled attenuation parameter
  • the LFP measurement is obtained in a second liver sample.
  • the LFP measurement comprises a liver triglyceride measurement.
  • the LFP measurement is obtained by an assay such as an immunoassay, a colorimetric
  • the LFP measurement or the LFP measurement is obtained using a scoring system upon a visual inspection of a sample such as a histological sample. In some embodiments, the LFP measurement or the LFP measurement is obtained using a stain with an affinity to fats, such as a lysochrome diazo dye.
  • the composition reduces the LFP measurement relative to the baseline LFP measurement.
  • the reduced LFP is measured in a second liver sample obtained from the subject after administering the composition to the subject.
  • the reduced LFP is measured directly in the subject after administering the composition to the subject.
  • the LFP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline LFP measurement.
  • the LFP measurement is decreased by about 10% or more, relative to the baseline LFP measurement.
  • the LFP 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 LFP measurement. In some embodiments, the LFP 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 LFP measurement. In some embodiments, the LFP measurement is decreased by no more than about 10%, relative to the baseline LFP measurement.
  • the LFP 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%, or no more than about 90% relative to the baseline LFP measurement. In some embodiments, the LFP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a liver fibrosis measurement.
  • the liver fibrosis measurement is a liver fibrosis score (LFS).
  • the LFS comprises a score of 0, 1, 2, 3, or 4, or a range of scores defined by any two of the aforementioned numbers.
  • the LFS comprises a score of 0-4.
  • the LFS is obtained using a scoring system exemplified in Table 4.
  • the LFS measurement is obtained noninvasively.
  • the LFS measurement is obtained by a medical imaging device such as a vibration-controlled transient elastography (VCTE) device, a shear wave elastography device, a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, or an ultrasound device.
  • a medical imaging device such as a vibration-controlled transient elastography (VCTE) device, a shear wave elastography device, a medical resonance imaging (MRI) device, a magnetic resonance spectroscopy device, a computed tomography device, or an ultrasound device.
  • the LFS measurement is obtained in a second liver sample.
  • the LFS is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the LFS is obtained using one or more indirect markers or measures of liver fibrosis such as an aspartate aminotransferase-to- platelet ratio index (APRI), a Fibrosis-4 (FIB-4) index, a FibroIndex, a Forns Index, a Hepascore, or a FibroTest.
  • the LFS is obtained using one or more indirect markers or measures of liver fibrosis such as a FIBROSpect test or a FIBROSpect II test.
  • the LFS is obtained by RT-qPCR or RNA sequencing of one or more fibrosis-related genes such as a collagen gene.
  • the LFS or the LFS is obtained using a scoring system upon a visual inspection of a sample such as a histological sample.
  • the LFS or the LFS is obtained using a stain with an affinity to collagen.
  • the composition reduces the LFS relative to the baseline LFS.
  • the reduced LFS is measured in a second liver sample obtained from the subject after administering the composition to the subject.
  • the reduced LFS is measured directly in the subject after administering the composition to the subject.
  • the LFS is decreased by 1 relative to the baseline LFS.
  • the LFS is decreased by 2 relative to the baseline LFS.
  • the LFS is decreased by 3 relative to the baseline LFS.
  • the LFS is decreased by 4 relative to the baseline LFS.
  • the LFS is decreased by 1 or more, relative to the baseline LFS.
  • the LFS is decreased by 2 or more, relative to the baseline LFS. In some embodiments, the LFS is decreased by 3 more, relative to the baseline LFS. In some embodiments, the LFS is decreased by no more than 1, relative to the baseline LFS. In some embodiments, the LFS is decreased by no more than 2, relative to the baseline LFS. In some embodiments, the LFS is decreased by no more than 3, relative to the baseline LFS. In some embodiments, the LFS is decreased by no more than 4, relative to the baseline LFS. In some embodiments, the LFS is decreased by 1, 2, 3, or 4, or by a range defined by any of the two aforementioned numbers.
  • the liver fibrosis measurement is a nonalcoholic fatty liver disease (NAFLD) fibrosis score.
  • a NAFLD fibrosis score may take into account laboratory test values such as platelet count, albumin, and AST/ ALT ratio, and patient characteristics such as BMI, and diabetes status.
  • a NAFLD fibrosis score below -1.455 may be indicative of no fibrosis, mild fibrosis, or moderate fibrosis.
  • a NAFLD fibrosis score between -1.455 and 0.675 may be indicative of severe fibrosis.
  • a NAFLD fibrosis score above 0.675 may be indicative of cirrhosis.
  • the composition reduces the NAFLD fibrosis score relative to the baseline NAFLD fibrosis score.
  • the NAFLD fibrosis score is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline NAFLD fibrosis score.
  • the NAFLD fibrosis score is decreased by about 10% or more, relative to the baseline NAFLD fibrosis score.
  • the NAFLD fibrosis score 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 NAFLD fibrosis score.
  • the NAFLD fibrosis score 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 NAFLD fibrosis score. In some embodiments, the NAFLD fibrosis score is decreased by no more than about 10%, relative to the baseline NAFLD fibrosis score. In some embodiments, the NAFLD fibrosis score 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 NAFLD fibrosis score.
  • the NAFLD fibrosis score 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 measurement is a non-alcoholic fatty liver disease (NAFLD) activity score.
  • the NAFLD activity score comprises a numerical value such as a number of points. In some embodiments, the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a range defined by any two of the aforementioned numerical values. In some embodiments, the numerical value is 0-8.
  • the NAFLD activity score comprises a steatosis grade such as a liver fat percentage. In some embodiments, a steatosis grade ⁇ 5% comprises 0 points in the NAFLD activity score. In some embodiments, a steatosis grade of 5-33% comprises 1 point in the NAFLD activity score.
  • a steatosis grade of 34-66% comprises 2 points in the NAFLD activity score. In some embodiments, a steatosis grade of > 66% comprises 3 points in the NAFLD activity score.
  • the NAFLD activity score comprises a lobular inflammation grade. In some embodiments, the lobular inflammation grade comprises an assessment of inflammatory foci. In some embodiments, a lobular inflammation grade comprising 0 foci comprises 0 points in the NAFLD activity score. In some embodiments, a lobular inflammation grade comprising 1 focus per afield (such as a 20x field or a 200x field) comprises 1 point in the NAFLD activity score.
  • a lobular inflammation grade comprising 2-4 foci per field comprises 2 points in the NAFLD activity score. In some embodiments, a lobular inflammation grade comprising > 4 foci per field comprises 3 points in the NAFLD activity score.
  • the NAFLD activity score comprises a liver cell injury grade such as an amount of ballooning cells. In some embodiments, a liver cell injury comprising no ballooning cells comprises 0 points in the NAFLD activity score. In some embodiments, a liver cell injury comprising some new balloon cells comprises 1 point in the NAFLD activity score. In some embodiments, a liver cell injury comprising many ballooning cells or prominent ballooning comprises 2 points in the NAFLD activity score. In some embodiments, the NAFLD activity score is obtained invasively, based on histology, and/or in a liver biopsy.
  • the composition reduces the NAFLD activity score relative to the baseline NAFLD activity score.
  • the reduced NAFLD activity score is measured in a second liver sample obtained from the subject after administering the composition to the subject.
  • the NAFLD activity score is decreased by 1 relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by 2 relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by 3 relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by 4 relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by 5 relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by 6 relative to the baseline NAFLD activity score. In some embodiments, the NAFLD activity score is decreased by 7 relative to the baseline NAFLD activity score. In some embodiments, the NAFLD activity score is decreased by 8 relative to the baseline NAFLD activity score. In some embodiments, the NAFLD activity score is decreased by 1 or more, relative to the baseline NAFLD activity score. In some embodiments, the NAFLD activity score is decreased by 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more, relative to the baseline NAFLD activity score.
  • the NAFLD activity score is decreased by no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, or no more than 8, relative to the baseline NAFLD activity score. In some embodiments, the NAFLD activity score is decreased by 1, 2, 3, 4, 5, 6, 7, or 8, or by a range defined by any of the two aforementioned numbers.
  • the measurement is a gamma-glutamyl transferase (GGT) measurement.
  • the GGT measurement is a GGT concentration.
  • the GGT measurement is a blood GGT measurement.
  • the GGT measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a chromatography assay, or a fluorescence assay.
  • the composition reduces the GGT measurement relative to the baseline GGT measurement.
  • the reduced GGT is measured in a second blood sample, plasma sample, or serum sample obtained from the subject after administering the composition to the subject.
  • the GGT measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline GGT measurement.
  • the GGT measurement is decreased by about 10% or more, relative to the baseline GGT measurement.
  • the GGT 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 GGT measurement.
  • the GGT 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 GGT measurement. In some embodiments, the GGT measurement is decreased by no more than about 10%, relative to the baseline GGT measurement. In some embodiments, the GGT 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 GGT measurement. In some embodiments, the GGT 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 measurement is a hair count.
  • the hair count is a total hair count.
  • the total hair count may include a vellus hair count and a non-vellus hair count.
  • the hair count is a vellus hair count.
  • the hair count is a non- vellus hair count.
  • the hair count is determined in an area of skin.
  • the hair count is normalized based on the area of skin.
  • the hair count is assessed using photography.
  • the hair count is assessed by phototrichogram.
  • the hair count is assessed by a macrophotography analysis.
  • the composition increases the hair count relative to the baseline hair count.
  • the increase is measured in the subject after administering the composition to the subject. In some embodiments, the increase is measured directly on the subject after administering the composition to the subject.
  • the hair count is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hair count. In some embodiments, the hair count is increased by about 10% or more, relative to the baseline hair count. In some embodiments, the hair count 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 hair count.
  • the hair count 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 hair count. In some embodiments, the hair count 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 hair count. In some embodiments, the hair count is increased by no more than about 10%, relative to the baseline hair count.
  • the hair count 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 hair count. In some embodiments, the hair count 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 hair count.
  • the hair count is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a hair thickness measurement.
  • the hair thickness measurement is determined in an area of skin.
  • the hair thickness measurement comprises a width of an individual hair.
  • the hair thickness measurement comprises widths of multiple individual hairs.
  • the hair thickness measurement comprises an average of the widths of the multiple individual hairs.
  • the hair thickness measurement comprises a median of the widths of the multiple individual hairs.
  • the hair thickness measurement may include a vellus hair thickness measurement.
  • the hair thickness measurement may include a non- vellus hair thickness measurement.
  • the hair thickness measurement is assessed using photography.
  • the hair thickness measurement is assessed by phototrichogram.
  • the hair thickness measurement is assessed by a macrophotography analysis.
  • the composition increases the hair thickness measurement relative to the baseline hair thickness measurement.
  • the increase is measured in a second tissue sample (e.g., a skin sample as described herein) obtained from the subject after administering the composition to the subject.
  • the increase is measured directly on the subject after administering the composition to the subject.
  • the hair thickness measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hair thickness measurement.
  • the hair thickness measurement is increased by about 10% or more, relative to the baseline hair thickness measurement.
  • the hair thickness 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 hair thickness measurement. In some embodiments, the hair thickness 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 hair thickness measurement. In some embodiments, the hair thickness 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 hair thickness measurement. In some embodiments, the hair thickness measurement is increased by no more than about 10%, relative to the baseline hair thickness measurement.
  • the hair thickness 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 hair thickness measurement. In some embodiments, the hair thickness 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 hair thickness measurement.
  • the hair thickness measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a hair density measurement.
  • the hair density measurement is determined in an area of skin.
  • the hair density measurement comprises a number of hair in the area of skin.
  • the hair density measurement comprises the number of hair in the area of skin divided by the area of skin.
  • the hair density measurement may include a vellus hair density measurement.
  • the hair density measurement may include a non- vellus hair density measurement.
  • the hair density measurement is assessed using photography.
  • the hair density measurement is assessed by phototrichogram.
  • the hair density measurement is assessed by a macrophotography analysis.
  • the composition increases the hair density measurement relative to the baseline hair density measurement.
  • the increase is measured in a second tissue sample (e.g., a skin sample as described herein) obtained from the subject after administering the composition to the subject.
  • the increase is measured directly on the subject after administering the composition to the subject.
  • the hair density measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline hair density measurement.
  • the hair density measurement is increased by about 10% or more, relative to the baseline hair density measurement.
  • the hair density 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 hair density measurement. In some embodiments, the hair density 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 hair density measurement. In some embodiments, the hair density 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 hair density measurement. In some embodiments, the hair density measurement is increased by no more than about 10%, relative to the baseline hair density measurement.
  • the hair density 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 hair density measurement. In some embodiments, the hair density 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 hair density measurement.
  • the hair density measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a S0S2 protein measurement.
  • the S0S2 protein measurement comprises a S0S2 protein level.
  • the S0S2 protein level is indicated as a mass or percentage of S0S2 protein per sample weight.
  • the S0S2 protein level is indicated as a mass or percentage of S0S2 protein per sample volume.
  • the S0S2 protein level is indicated as a mass or percentage of S0S2 protein per total protein within the sample.
  • the S0S2 protein measurement is a tissue S0S2 protein measurement.
  • tissue S0S2 protein measurements include a liver S0S2 protein measurement, a kidney S0S2 protein measurement, an eye S0S2 protein measurement, or a adipose tissue S0S2 protein measurement.
  • the S0S2 protein measurement is a circulating S0S2 protein measurement.
  • the S0S2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the composition reduces the S0S2 protein measurement relative to the baseline S0S2 protein measurement.
  • the reduction is measured in a second sample (e.g., a tissue sample such as liver, kidney, adipose, or eye tissue) obtained from the subject after administering the composition to the subject.
  • the S0S2 protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline S0S2 protein measurement.
  • the S0S2 protein measurement is decreased by about 10% or more, relative to the baseline S0S2 protein measurement.
  • the S0S2 protein 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 S0S2 protein measurement. In some embodiments, the S0S2 protein 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 S0S2 protein measurement. In some embodiments, the S0S2 protein measurement is decreased by no more than about 10%, relative to the baseline S0S2 protein measurement.
  • the S0S2 protein 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%, or no more than about 90%relative to the baseline S0S2 protein measurement. In some embodiments, the S0S2 protein measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a S0S2 mRNA measurement.
  • the S0S2 mRNA measurement comprises a S0S2 mRNA level.
  • the S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per sample weight.
  • the S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per sample volume.
  • the S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per total mRNA within the sample.
  • the S0S2 mRNA level is indicated as a mass or percentage of S0S2 mRNA per total nucleic acids within the sample. In some embodiments, the S0S2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the S0S2 mRNA measurement is a tissue S0S2 mRNA measurement. Examples of tissue S0S2 mRNA measurements include a liver S0S2 mRNA measurement, a kidney S0S2 mRNA measurement, an eye S0S2 mRNA measurement, or a adipose tissue S0S2 mRNA measurement.
  • the S0S2 mRNA measurement is a circulating S0S2 mRNA measurement.
  • the S0S2 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 S0S2 mRNA.
  • the composition reduces the S0S2 mRNA measurement relative to the baseline S0S2 mRNA measurement.
  • the reduction is measured in a second sample (e.g., a tissue sample such as liver, kidney, adipose, or eye tissue) obtained from the subject after administering the composition to the subject.
  • the second sample may comprise or consist of hepatocytes.
  • the sample may comprise or consist of podocytes.
  • the S0S2 mRNA measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline S0S2 mRNA measurement.
  • the S0S2 mRNA measurement is decreased by about 10% or more, relative to the baseline S0S2 mRNA measurement. In some embodiments, the S0S2 mRNA 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 S0S2 mRNA measurement. In some embodiments, the S0S2 mRNA 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 S0S2 mRNA measurement.
  • the S0S2 mRNA measurement is decreased by no more than about 10%, relative to the baseline S0S2 mRNA measurement. In some embodiments, the S0S2 mRNA 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%, or no more than about 90%relative to the baseline S0S2 mRNA measurement. In some embodiments, the S0S2 mRNA measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or by a range defined by any of the two aforementioned percentages.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative ⁇ qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute.
  • Detecting the presence of can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • a “subject” can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “about” a number refers to that number plus or minus 10% of that number.
  • the term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • mRNA means the presently known mRNA transcript(s) of a targeted gene, and any further transcripts which may be elucidated.
  • dsRNA RNA
  • siRNA agent agents that can mediate silencing of a target RNA
  • a target RNA e.g., mRNA, e.g., a transcript of a gene that encodes a protein.
  • the target RNA is SOS.
  • mRNA may also be referred to herein as mRNA to be silenced.
  • a gene is also referred to as a target gene.
  • the RNA to be silenced is an endogenous gene or a pathogen gene.
  • RNAs other than mRNA e. g. , tRNAs, and viral RNAs, can also be targeted.
  • the phrase "mediates RNAi” refers to the ability to silence, in a sequence specific manner, a target RNA. While not wishing to be bound by theory, it is believed that silencing uses the RNAi machinery or process and a guide RNA, e.g., an siRNA agent.
  • “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of complementarity such that stable and specific binding occurs between a compound described herein and a target RNA molecule.
  • a dsRNA agent is "sufficiently complementary" to a target RNA, e.g., a target mRNA, such that the dsRNA agent silences production of protein encoded by the target mRNA.
  • the dsRNA agent is "exactly complementary" to a target RNA, e.g., the target RNA and the dsRNA duplex agent anneal, for example to form a hybrid made exclusively of Watson- Crick base pairs in the region of exact complementarity.
  • a "sufficiently complementary" target RNA can include an internal region (e.g., of at least 10 nucleotides) that is exactly complementary to a target RNA.
  • the dsRNA agent specifically discriminates a single- nucleotide difference. In this case, the dsRNA agent only mediates RNAi if exact complementary is found in the region (e.g., within 7 nucleotides of) the single-nucleotide difference.
  • oligonucleotide refers to a nucleic acid molecule (RNA or DNA) for example of length less than 100, 200, 300, or 400 nucleotides.
  • oligonucleotide refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof.
  • oligonucleotide also includes linear or circular oligomers of natural and/or modified monomers or linkages, including deoxyribonucleosides, ribonucleosides, substituted and alpha-anomeric forms thereof, peptide nucleic acids (PNA), locked nucleic acids (LNA), phosphorothioate, methylphosphonate, and the like.
  • Oligonucleotides are capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer-to-monomer interactions, such as Watson-Crick type of base pairing, Hoogsteen or reverse Hoogsteen types of base pairing, or the like.
  • the oligonucleotide is "chimeric", that is, composed of different regions.
  • "Chimeric" oligonucleotides contain two or more chemical regions, for example, DNA region(s), RNA region(s), PNA region(s), etc. Each chemical region is made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotides compound.
  • These oligonucleotides typically comprise at least one region wherein the oligonucleotide is modified in order to exhibit one or more desired properties.
  • the desired properties of the oligonucleotide include, but are not limited, for example, to increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. Different regions of the oligonucleotide may therefore have different properties.
  • Chimeric oligonucleotides can be formed as mixed structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide analogs.
  • the oligonucleotide can comprise or be composed of regions that can be linked in "register", that is, when the monomers are linked consecutively, as in native DNA, or linked via spacers.
  • the spacers are intended to constitute a covalent "bridge” between the regions and have, in some cases, a length not exceeding about 100 carbon atoms.
  • the spacers may carry different functionalities, for example, having positive or negative charge, carry special nucleic acid binding properties (intercalators, groove binders, toxins, fluorophores etc.), being lipophilic, inducing special secondary structures like, for example, alanine containing peptides that induce alpha-helices.
  • oligonucleotide specific for or "oligonucleotide which targets” refers to an oligonucleotide having a sequence (i) capable of forming a stable complex with a portion of the targeted gene, or (ii) capable of forming a stable duplex with a portion of a mRNA transcript of the targeted gene. Stability of the complexes and duplexes can be determined by theoretical calculations and/or in vitro assays.
  • target nucleic acid encompasses DNA, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA, coding, noncoding sequences, sense and antisense polynucleotides.
  • RNA including pre-mRNA and mRNA
  • cDNA derived from such RNA
  • coding, noncoding sequences sense and antisense polynucleotides.
  • antisense The functions of DNA that are modulated include, for example, replication and transcription.
  • RNA that are modulated include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA.
  • the overall effect of such interference with target nucleic acid function is modulation of the expression of an encoded product or oligonucleotides.
  • RNA interference "RNAi” is mediated by double stranded RNA (dsRNA) molecules that have sequence- specific homology to their "target" nucleic acid sequences.
  • the mediators are 5-25 nucleotide "small interfering" RNA duplexes (siRNAs).
  • siRNAs are derived from the processing of dsRNA by an RNase enzyme known as Dicer. siRNA duplex products are recruited into a multi-protein siRNA complex termed RISC (RNA Induced Silencing Complex).
  • a RISC is then believed to be guided to a target nucleic acid (suitably mRNA), where the siRNA duplex interacts in a sequence-specific way to mediate cleavage in a catalytic fashion.
  • Small interfering RNAs can be synthesized and used. Small interfering RNAs for use in the methods herein suitably comprise between about 1 to about 50 nucleotides (nt). In examples of nonlimiting embodiments, siRNAs can comprise about 5 to about 40 nt, about 5 to about 30 nt, about 10 to about 30 nt, about 15 to about 25 nt, or about 20-25 nucleotides.
  • selection of appropriate oligonucleotides is facilitated by using computer programs that automatically align nucleic acid sequences and indicate regions of identity or homology. Such programs are used to compare nucleic acid sequences obtained, for example, by searching databases such as GenBank or by sequencing PCR products. Comparison of nucleic acid sequences from a range of species allows the selection of nucleic acid sequences that display an appropriate degree of identity between species.
  • Southern blots are performed to allow a determination of the degree of identity between genes in target species and other species. By performing Southern blots at varying degrees of stringency, as is well known in the art, it is possible to obtain an approximate measure of identity.
  • enzymatic RNA is meant as an RNA molecule with enzymatic activity.
  • Enzymatic nucleic acids ribozymes
  • the enzymatic nucleic acid first recognizes and then binds a target RNA through base pairing, and once bound to the correct site, acts enzymatically to cut the target RNA.
  • decoy RNA is meant as an RNA molecule that mimics the natural binding domain for a ligand.
  • the decoy RNA therefore competes with natural binding targets for the binding of a specific ligand.
  • over-expression of HIV trans-activation response (TAR) RNA can act as a "decoy” and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA.
  • TAR HIV trans-activation response
  • "monomers” typically indicate monomers linked by phosphodi ester bonds or analogs thereof to form oligonucleotides ranging in size from a few monomeric units, e.g., from about 3-4, to about several hundreds of monomeric units.
  • Analogs of phosphodiester linkages include: phosphorothioate, phosphor odi thioate, methylphosphonates, phosphoroselenoate, phosphoramidate, and the like, as more fully described below.
  • nucleotide covers naturally occurring nucleotides as well as non- naturally occurring nucleotides. It should be clear to the person skilled in the art that various nucleotides which previously have been considered “non- naturally occurring” have subsequently been found in nature. Thus, “nucleotides” includes not only the known purine and pyrimidine heterocycles-containing molecules, but also heterocyclic analogues and tautomers thereof.
  • nucleotides are molecules containing adenine, guanine, thymine, cytosine, uracil, purine, xanthine, A aminopurine, 8-oxo- N6-memyladenine, 7 -deazaxanthine, 7- deazaguanine, N4,N4-ethanocytosin, N6,N6- ethano-2,6- diaminopurine, 5 -methylcytosine, 5-(C3-C6)-alkynylcytosine, 5-fluorouracil, 5- bromouracil, pseudoisocytosine, 2-hydroxy-5-memyl-4-triazolopvridin, isocytosine, isoguanin, inosine and the "non-naturally occurring" nucleotides described in Benner et al., U.
  • nucleotide is intended to cover every and all of these examples as well as analogues and tautomers thereof.
  • Especially interesting nucleotides are those containing adenine, guanine, thymine, cytosine, and uracil, which are considered as the naturally occurring nucleotides in relation to therapeutic and diagnostic application in humans.
  • Nucleotides include the natural 2'-deoxy and 2'-hydroxyl sugars, as well as their analogs.
  • “analogs” in reference to nucleotides includes synthetic nucleotides having modified base moieties and/or modified sugar moieties. Such analogs include synthetic nucleotides designed to enhance binding properties, e.g., duplex or triplex stability, specificity, or the like.
  • “hybridization” means the pairing of at least substantially complementary strands of oligomeric compounds.
  • One mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleotides) of the strands of oligomeric compounds.
  • adenine and thymine are complementary nucleotides which pair through the formation of hydrogen bonds. Hybridization can occur under varying circumstances.
  • a compound of the disclosure is "specifically hybridizable" when binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause a modulation of function and/or activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the compound to non-target nucleic acid sequences under conditions in which specific binding is desired, i. e. , under physiological conditions in the case of in vivo assays or therapeutic treatment, and under conditions in which assays are performed in the case of in vitro assays.
  • stringent hybridization conditions or “stringent conditions” refers to conditions under which a compound will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances and "stringent conditions" under which oligomeric compounds hybridize to a target sequence are determined by the nature and composition of the oligomeric compounds and the assays in which they are being investigated. In some cases, stringent hybridization conditions comprise low concentrations ( ⁇ 0.
  • the hybridization rate decreases 1. 1% for each 1% formamide.
  • An example of a high stringency hybridization condition is 0. IX sodium chloride-sodium citrate buffer (SSC)/0.1% (w/v) SDS at 60° C for 30 minutes.
  • complementary refers to the capacity for precise pairing between two nucleotides on one or two oligomeric strands. For example, if a nucleobase at a certain position of a compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, said target nucleic acid being a DNA, RNA, or oligonucleotide molecule, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid may be considered to be a complementary position.
  • oligomeric compound and the further DNA, RNA, or oligonucleotide molecule are complementary to each other when a sufficient number of complementary positions in each molecule are occupied by nucleotides which can hydrogen bond with each other.
  • “specifically hybridizable” and “complementary” are terms which may be used to indicate a sufficient degree of precise pairing or complementarity over a sufficient number of nucleotides such that stable and specific binding occurs between the oligomeric compound and a target nucleic acid.
  • oligomeric compounds need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable.
  • an oligonucleotide may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).
  • oligomeric compounds disclosed herein comprise at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% sequence complementarity to a target region within the target nucleic acid sequence to which they are targeted.
  • a compound in which 18 of 20 nucleotides of the compound are complementary to a target region, and would therefore specifically hybridize would represent 90 percent complementarity.
  • the remaining noncomplementary nucleotides may be clustered or interspersed with complementary nucleotides and need not be contiguous to each other or to complementary nucleotides.
  • a compound which is 18 nucleotides in length having 4 (four) noncomplementary nucleotides which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present disclosure.
  • Percent complementarity of a compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art. Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman.
  • the term "Thermal Melting Point (Tm)” refers to the temperature, under defined ionic strength, pH, and nucleic acid concentration, at which 50% of the oligonucleotides complementary to the target sequence hybridize to the target sequence at equilibrium.
  • stringent conditions will be those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short oligonucleotides (e.g., 10 to 50 nucleotide). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide.
  • modulation means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene.
  • the term "variant”, when used in the context of a polynucleotide sequence, may encompass a polynucleotide sequence related to a wild type gene. This definition may also include, for example, "allelic,” “splice,” “species,” or “polymorphic” variants.
  • a splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing.
  • the corresponding polypeptide may possess additional functional domains or an absence of domains.
  • Species variants are polynucleotide sequences that vary from one species to another. Of particular utility are variants of wild type gene products.
  • Variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. Any given natural or recombinant gene may have none, one, or many allelic forms. Common mutational changes that give rise to variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.
  • polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass "single nucleotide polymorphisms" (SNPs,) or single base mutations in which the polynucleotide sequence varies by one base. The presence of SNPs may be indicative of, for example, a certain population with a propensity for a disease state, that is susceptibility versus resistance.
  • SNPs single nucleotide polymorphisms
  • Derivative polynucleotides include nucleic acids subjected to chemical modification, for example, replacement of hydrogen by an alkyl, acyl, or amino group.
  • Derivatives e.g., derivative oligonucleotides, may comprise non- naturally -occurring portions, such as altered sugar moi eties or intersugar linkages. Exemplary among these are phosphorothioate and other sulfur containing species which are known in the art.
  • Derivative nucleic acids may also contain labels, including radionucleotides, enzymes, fluorescent agents, chemiluminescent agents, chromogenic agents, substrates, co factors, inhibitors, magnetic particles, and the like.
  • C x -y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • a chemical moiety such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • Ci-ealkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from 1 to 6 carbons.
  • C x-y alkenyl and C x-y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon.
  • Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • a bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • a bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane.
  • a bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[l. l. l]pentanyl.
  • aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • cycloalkyl refers to a saturated ring in which each atom of the ring is carbon.
  • Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a cycloalkyl comprises three to ten carbon atoms.
  • a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example ⁇ adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo[l. l. l]pentanyl, and the like.
  • Cycloalkenyl refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-chloromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the haloalkyl radical is optionally further substituted as described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12- membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems,
  • a bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.
  • heteroaryl refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Huckel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benz
  • heterocycloalkyl refers to a saturated ring with carbon atoms and at least one heteroatom.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
  • heterocycloalkenyl refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings.
  • a heterocycloalkenyl comprises five to seven ring atoms.
  • the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine,
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e. g. , an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • a "derivative" polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment.
  • a derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.
  • any uracil (U) may be interchanged with any thymine (T), and vice versa.
  • any of the Us may be replaced with Ts.
  • an siRNA with a nucleic acid sequence comprising one or more Ts in some embodiments any of the Ts may be replaced with Us.
  • an oligonucleotide such as an siRNA disclosed herein comprises or consists of RNA.
  • the oligonucleotide may comprise or consist of DNA.
  • Nf e.g., Af, Cf, Gf, Tf, or Uf
  • dN e.g., dA, dC, dG, dT, or dU
  • n e.g., a, c, g, t, or u
  • s refers to a phosphate or phosphorothioate linkage.
  • a pyrimidine may include cytosine (C), thymine (T), or uracil (U).
  • a pyrimidine may include C or U.
  • a pyrimidine may include C or T.
  • a reference to a pyrimidine may include a nucleoside or nucleotide comprising the pyrimidine.
  • a purine may include guanine (G), inosine (I), or adenine (A).
  • a reference to a purine may include a nucleoside or nucleotide comprising a purine.
  • Example 1 Nonsynonymous Variants in the SOS2 Gene Demonstrate Protective Associations Across a Spectrum of Diseases and Traits
  • Applicant evaluated two missense variants (Table 5) in approximately 452,000 individuals with genotype data from the UK Biobank cohort for associations with a variety of traits.
  • the S0S2 burden is also associated with decreased risk of type 2 diabetes (T2D), use of diabetes medications, family history of diabetes and decreased hemoglobin A1C, suggesting that S0S2 inhibition may protect against diabetes (Table 7).
  • the S0S2 burden is also associated with decreased risk for obesity, decreased body mass index (BMI), decreased waist and hip circumference and decreased body fat percentage, suggesting that S0S2 inhibition may protect against obesity (Table 8).
  • the S0S2 burden is also associated with decreased risk of hypertension, decreased systolic and diastolic blood pressure (SBP and DBP), decreased mean arterial pressure (MAP) and decreased use of antihypertensive medications, suggesting that S0S2 inhibition may protect against hypertension. (Table 9).
  • the S0S2 burden is also associated with decreased risk of all-cause cerebrovascular disease, ischemic cerebrovascular disease and family history of stroke, suggesting that S0S2 inhibition may protect against cerebrovascular disease (Table 10).
  • the S0S2 burden is also associated with decreased blood urate, decreased risk of gout and decreased use of gout medications, suggesting that SOS2 inhibition may protect against gout and hyperuricemia (Table 11).
  • the SOS2 burden is also associated with increased estimated glomerular filtration rate (eGFR) and decreased blood creatinine, decreased blood urea nitrogen (BUN), decreased risk of chronic kidney disease (CKD), decreased risk of proteinuria and decreased urinary microalbumin, suggesting that SOS2 inhibition may protect against kidney disease (Table 12).
  • the S0S2 burden is associated with decreased risk of glaucoma, primary open-angle glaucoma (POAG), decreased use of glaucoma medications, decreased risk of surgery for glaucoma, decreased intraocular pressure and decreased vertical cup-disc ratio, suggesting that SOS2 inhibition may protect against glaucoma and ocular hypertension (Table 13).
  • the SOS2 burden is also associated with decreased risk of macular degeneration, diabetic retinopathy and decreased thickness of the retinal pigment epithelium (RPE), suggesting that SOS2 inhibition may protect against retinal disorders such as macular degeneration and diabetic retinopathy (Table 14).
  • Example 2 siRNA-mediated knockdown of SOS2 in PODO/TERT256 cell line
  • siRNAs will be targeted to S0S2 mRNA that may downregulate levels of S0S2 mRNA leading to a decrease in RAC1 protein activation, when administered to the cultured immortalized human podocyte cell line PODO/TERT256 (Evercyte Cat. No. CHT-033-0256).
  • the PODO/TERT256 cells will be seeded at 150,000 cells/mL into a Falcon 24- well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mL per well.
  • the S0S2 siRNA and negative control siRNA master mixes will be prepared.
  • the S0S2 siRNA master mix will contain 350 pL of Opti-MEM (ThermoFisher Cat. No. 4427037 - sl288 Lot No. AS02B02D) and 3.5 pL of a mixture of the two S0S2 siRNAs (10 pM stock).
  • the negative control siRNA master mix will contain 350 pL of Opti-MEM and 3.5 pL of negative control siRNA (ThermoFisher Cat. No. 4390843, 10 pM stock).
  • 3 pL of TransIT-X2 (Minis Cat. No. MIR-6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 51 pL of the appropriate master mix + TransIT-X2 is added to duplicate wells of PODO/TERT256 cells with a final siRNA concentration of 10 nM.
  • the reverse transcriptase reaction is performed using 22.5 pL of the lysate according to the manufacturer’s protocol. Samples are stored at -80°C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/SOS2 using a BioRad CFX96 Cat. No. 1855195). For the protein quantification, equivalent quantities (30-50 pg) of protein are separated by 10% SDS polyacrylamide gels and transferred to poly vinylidene fluoride membranes. Membranes are blocked with 5% nonfat milk and incubated overnight with the appropriate primary antibody at dilutions specified by the manufacturer.
  • the membranes are washed three times in TBST and incubated with the corresponding horseradish peroxidase conjugated secondary antibody at 1:5,000 dilution for 1 hr. Bound secondary antibody is detected using an enhanced chemiluminescence system.
  • Primary immunoblotting antibodies are: anti-GAPDH, anti-RACl, anti-GTP-RACl (Sigma, MO) and anti-SOS2 (Abeam, Cambridge, UK).
  • a decrease in S0S2 mRNA expression in the PODO/TERT256 cells is expected after transfection with the S0S2 siRNAs compared to S0S2 mRNA levels in PODO/TERT256 cells transfected with the non-specific control siRNA 48 hours after transfection.
  • Example 3 ASO-mediated knockdown of SOS2 in PODO/TERT256 cell line
  • ASOs will be targeted to S0S2 mRNA that may downregulate levels of S0S2 mRNA leading to a decrease in RAC1 protein activation, when administered to the cultured immortalized human podocyte cell line PODO/TERT256 (Evercyte Cat. No. CHT-033-0256).
  • the PODO/TERT256 cells will be seeded at 150,000 cells/mL into a Falcon 24- well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mL per well.
  • the S0S2 ASO and negative control ASO master mixes will be prepared.
  • the S0S2 ASO master mix will contain 350 pL of Opti-MEM (ThermoFisher Cat. No. 4427037 - sl288 Lot No. AS02B02D) and 3.5 pL of a mixture of the two S0S2 ASOs (10 pM stock).
  • the negative control ASO master mix will contain 350 pL of Opti-MEM and 3.5 pL of negative control ASO (ThermoFisher Cat. No. 4390843, 10 pM stock).
  • 3 pL of TransIT-X2 (Minis Cat. No. MIR-6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 51 pL of the appropriate master mix + TransIT-X2 is added to duplicate wells of PODO/TERT256 cells with a final ASO concentration of 10 nM.

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Abstract

L'invention concerne des compositions comprenant un oligonucléotide qui cible le facteur d'échange nucléotidique 2 de SOS Ras/Rho guanine (SOS2). L'oligonucléotide peut comprendre un petit ARN interférent (ARNsi) ou un oligonucléotide antisens (ASO). L'invention concerne également des procédés de traitement d'états associés à des mutations de SOS2 qui comprennent la fourniture d'un oligonucléotide qui cible SOS2 sur un sujet.
PCT/US2024/057128 2023-11-22 2024-11-22 Traitement de maladies et de troubles associés à sos2 Pending WO2025111565A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210238599A1 (en) * 2020-02-04 2021-08-05 Regeneron Pharmaceuticals, Inc. Treatment Of Ophthalmic Conditions With Son of Sevenless 2 (SOS2) Inhibitors
US20210363525A1 (en) * 2015-04-22 2021-11-25 Mina Therapeutics Limited Sarna compositions and methods of use
WO2022115383A1 (fr) * 2020-11-24 2022-06-02 Empirico Inc. Traitement de maladies et de troubles liés au sos2
US20220275368A1 (en) * 2019-08-12 2022-09-01 Interna Technologies B.V. New treatments involving mirna-193a
WO2022226377A1 (fr) * 2021-04-22 2022-10-27 Molecular Axiom, Llc Compositions et méthodes pour moduler des expressions géniques de sos

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210363525A1 (en) * 2015-04-22 2021-11-25 Mina Therapeutics Limited Sarna compositions and methods of use
US20220275368A1 (en) * 2019-08-12 2022-09-01 Interna Technologies B.V. New treatments involving mirna-193a
US20210238599A1 (en) * 2020-02-04 2021-08-05 Regeneron Pharmaceuticals, Inc. Treatment Of Ophthalmic Conditions With Son of Sevenless 2 (SOS2) Inhibitors
WO2022115383A1 (fr) * 2020-11-24 2022-06-02 Empirico Inc. Traitement de maladies et de troubles liés au sos2
WO2022226377A1 (fr) * 2021-04-22 2022-10-27 Molecular Axiom, Llc Compositions et méthodes pour moduler des expressions géniques de sos

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