Treatment of SOS2 related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets SOS Ras / Rho guanine nucleotide exchange factor 2 (SOS2). The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with SOS2 mutations that include providing an oligonucleotide that targets SOS2 to a subject.

Description

TREATMENT OF SOS2 RELATED DISEASES AND DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 602,157, filed November 22, 2023, which is incorporated by reference in its entirety.BACKGROUND

[0002] 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.SUMMARY

[0003] In certain aspects, described herein is a 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. In some embodiments, 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.

[0004] In certain aspects, described herein is a 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. In some embodiments, the blood urate measurement is decreased by about 10% or more, as compared to prior to administration.

[0005] In certain aspects, described herein is a 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. In some embodiments, 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.

[0006] In certain aspects, described herein is 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 strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468. In some embodiments, 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.

[0007] In certain aspects, described herein is a 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. In some embodiments, 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.

[0008] In certain aspects, described herein is a 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. In some embodiments, 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.

[0009] In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sensestrand 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. In certain aspects, described herein is a 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 . In certain aspects, described herein is a 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 . In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof. In some embodiments, 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. In some embodiments, the lipid comprisessome embodiments, the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand, an arginine-glycine-aspartic acid (RGD) peptide, or a cholesterol ligand. In some embodiments, the oligonucleotide comprises a GalNAcligand. In some embodiments, the GalNAc ligand comprises the structure:, wherein J is the oligonucleotide. In some embodiments, described herein method of treating 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 in a subject in need thereof comprising administering to the subject a composition described herein.DETAILED DESCRIPTION OF THE INVENTION

[0010] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease, and provide applicable treatments. A GWAS can utilize genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional conceptin design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0011] Functional annotation of variants and / or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease -causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0012] Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend on several factors including the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, kidney, liver, adipocyte, or eye) and a relevant indication.

[0013] 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. In particular, it is shown here that 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.

[0014] Disclosed herein are compositions comprising an oligonucleotide that targets S0S2. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating 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, nonalcoholic fatty liver disease, fibrotic liver disease, liver fibrosis, cirrhosis, or hair loss (e.g., androgenetic alopecia) by providing an oligonucleotide that targets S0S2 to a subject in need thereof.I. COMPOSITIONS

[0015] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets SOS Ras / Rho guanine nucleotide exchange factor 2 (S0S2). In some embodiments, the composition consists of an oligonucleotide that targets S0S2. In some embodiments, the oligonucleotide reduces S0S2 mRNA expression in the subject. In some embodiments, 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. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein.

[0016] 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. In some embodiments, 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. In some embodiments, the cell is a liver cell (e.g., hepatocyte), kidney cell (e.g., podocyte), eye cell, or adipocyte. In some embodiments, the tissue is liver, kidney, eye, or adipose tissue. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0017] In some embodiments, 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. In some embodiments, the cell is a liver cell (e.g., hepatocyte), kidney cell (e.g., podocyte), eye cell, or adipocyte. In some embodiments, the tissue is liver, kidney, eye, or adipose tissue. In some embodiments,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. In some embodiments, the SOS2 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, 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. In some embodiments, 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.

[0018] In some embodiments, the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a kidney disease-related parameter. In some embodiments, the kidney disease comprises chronic kidney disease (CKD). In some embodiments, 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. 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. In some embodiments, 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. In some embodiments, 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.

[0019] In some embodiments, 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). In some embodiments, 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. In some embodiments, the kidney disease-related parameter is increased by about 10% or more, as compared to prior to administration. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0020] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 isdecreased 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. In some embodiments, 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. In some embodiments, 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.

[0021] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0022] In some embodiments, 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 intraocularpressure measurement. The glaucoma-related parameter may include a cup-disc ratio. The glaucoma related parameter may include optic nerve head cupping. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0023] In some embodiments, 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. In some embodiments, 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. In some embodiments, the glaucoma-related parameter is increased by about 10% or more, as compared to prior to administration. In some embodiments, 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. In some embodiments, 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. In some embodiments, the glaucoma-related parameter is increased by no more than about 200%, no more than about 300%, no more than about400%, 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. 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%, 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.

[0024] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the macular degeneration / diabetic retinopathy-related parameter is decreased by no more than about 10%, as compared to prior toadministration. 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. In some embodiments, 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.

[0025] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0026] In some embodiments, the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a metabolic disorder-related parameter. In some embodiments, the metabolic disorder comprises obesity. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0027] In some embodiments, the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a liver disease-related parameter. In some embodiments, the liver disease comprises fibrotic liver disease. In some embodiments, the liver disease comprises liver fibrosis. In some embodiments, the liver disease comprises cirrhosis. In some embodiments, 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. In some embodiments, 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. In some embodiments, the liver disease-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, 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. In some embodiments, 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.

[0028] In some embodiments, the composition comprises an oligonucleotide that targets S0S2 and when administered to a subject in an effective amount decreases a hair loss-related parameter. In some embodiments, 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. In some embodiments, 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. In some embodiments, the hair loss-related parameter is decreased by about 10% or more, as compared to prior to administration. In some embodiments, 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. In some embodiments, 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. Insome embodiments, 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.A. siRNAs

[0029] In some embodiments, 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). In some embodiments, 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.

[0030] In some embodiments, 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. In some embodiments, 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. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 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.

[0031] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0032] In some embodiments, 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. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0033] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0034] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0035] In some embodiments, 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. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human S0S2 mRNA.

[0036] In some embodiments, 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. In some embodiments, 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.

[0037] In some embodiments, 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. In some embodiments, 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.

[0038] In some embodiments, 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. In some embodiments, 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. In some embodiments, the siRNA binds with a human S0S2mRNA 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. In some embodiments, 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. 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 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.

[0039] In some embodiments, 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). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0040] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-5490. In some embodiments, 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. 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, 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 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: 1-5490.

[0041] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11274-11303. In some embodiments, 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. 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, 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.

[0042] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11354-11383. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1- 5460, 11274-11303, and 11354-11383 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 13082-13402 is modified to an A. In some embodiments, 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. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an A. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to a T or U. In some embodiments, position 1 (fromthe 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an G. In some embodiments, 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. In some embodiments, 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. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an G. In some embodiments, 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. In some embodiments, position 14 (fromthe 5’ end) of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an C. In some embodiments, 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. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1-5460, 11274-11303, and 11354-11383 is modified to an C.

[0044] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 5491-10980. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 5491-10980, at least80% 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. 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, 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.

[0045] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11304-11333. In some embodiments, 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. 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, 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.

[0046] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11384-11413. In some embodiments, 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. 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, 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.

[0047] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of 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.

[0048] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strandsequence 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.

[0049] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of 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.

[0050] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of 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.

[0051] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, atleast 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of 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.

[0052] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of 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.

[0053] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G. The sense strand or antisense strand may comprise any modifications describedherein. 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.

[0054] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset H. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset H. In some embodiments, 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. In some embodiments, 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. 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 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.

[0055] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset I. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset I. In some embodiments, 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. In some embodiments, 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. 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 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.

[0056] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset J. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sensestrand or antisense strand sequence of subset J. In some embodiments, 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. In some embodiments, 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. 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 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.

[0057] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset K. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset K. In some embodiments, 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. In some embodiments, 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. 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 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.

[0058] 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. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A-subset K. 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 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 ofsubset 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.

[0059] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 28. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 28. In some embodiments, 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. In some embodiments, 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. 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 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.

[0060] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 32. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 32. In some embodiments, 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. In some embodiments, 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. 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 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.

[0061] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 35. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 35. In some embodiments, 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. In some embodiments, 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. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strandsequence 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.

[0062] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 38. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 38. In some embodiments, 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. In some embodiments, 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. 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 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.

[0063] In some embodiments, 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. In some embodiments, 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, 744, 1036, 1056, 1178, 1521, 2148, 2151, 2152, 2158, 2619, 2882, 2883, 2884, 3042, 3305, 3969, 4216, 4305 or 4309, or at least 95% 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0064] In some embodiments, 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. In some embodiments, 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, 8373, 8374, 8532, 8795, 9459, 9706, 9795, or 9799, at least 90% 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, or at least 95% 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0065] In some embodiments, 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. In some embodiments, 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, 3231, 3259, 3333, 3487, 3491, 3586, 3587, or 3756, 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: 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0066] In some embodiments, 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. In some embodiments, 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, 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 90% 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, or at least 95% 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.B. ASOs

[0067] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or 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.

[0068] In some embodiments, 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. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 11253.C. Oligonucleotide Modifications

[0069] In some embodiments, 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. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphor odi thioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0070] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 -36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has thesame sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothi oates at the 5’ and 3’ ends.

[0071] In some embodiments, 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. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, 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 linkages.

[0072] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, 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 In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'- 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. In some embodiments, 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. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'- O- aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, themodified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, 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.

[0073] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:3' nucleotide5’ nucleotide wherein the base can be any pyrimidine or purine.

[0074] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0075] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:methylphosphonate 2’-O-Methyl Uridine).

[0076] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 -36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothi oates at the 5’ and 3’ ends.

[0077] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0078] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, orattached to a 3’ end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly- Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides. For example, the RGD peptide may include 2, 3, or 4 RGD peptides.

[0079] In some embodiments, 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. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0080] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’ -fluoro modified nucleoside, a 2’-O-Methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’ -fluoro modified nucleoside, a 2’ -O- Methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’ -fluoro modified nucleoside, a 2’-O-Methyl modified nucleoside, and 2’-O- methoxy ethyl. In some embodiments, the sense strand comprises at least a 2’ -fluoro modified nucleoside, a 2’-O-Methyl modified nucleoside, and 2’-O-methoxyethyl.

[0081] In some embodiments, the antisense strand is combination of 2’ -fluoro and 2’-O-Methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’ -fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’ -fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0082] 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.

[0083] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O- 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. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, the sense strand may include a 2’ -deoxy nucleoside.

[0084] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’ -fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2 ’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’ -fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’ -fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’ -O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside.

[0085] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’ - fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro; all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides comprise 2’ - fluoro. In some embodiments, all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O- methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides aremodified 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.

[0086] In some embodiments, 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.

[0087] In some embodiments, 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. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[0088] In some embodiments, 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.

[0089] In some embodiments, 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.

[0090] 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.

[0091] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’ -O-methyl modifiedpurines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’ -methyl modification may be included, and vice versa.

[0092] In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines.

[0093] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0094] In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’- fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’ -O-methyl modified purines. Insome 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. In some embodiments, 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.

[0095] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0096] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group includes a cell receptor ligand, such as an integrin targeting ligand. Integrins may include a family of transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. In some embodiments, the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 (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.

[0097] In some embodiments, 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). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the oligonucleotide-integrin targeting ligand conjugates areselectively internalized by chondrocytes, either through receptor-mediated endocytosis or by other means.

[0098] In some embodiments, an oligonucleotide that targets S0S2 further comprises a targeting ligand that targets a receptor which mediates delivery to a specific CNS tissue. In some embodiments, the targeting ligand is conjugated to the oligonucleotide. In one embodiment, 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. In one embodiment, the targeting ligand is selected from the group consisting of trans-retinol, RGD peptide, LDL receptor ligand, and carbohydrate-based ligands. In one embodiment, 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).

[0099] Examples of targeting groups useful for delivering the oligonucleotide that include integrin targeting ligands may be based upon peptides or peptide mimics containing an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide, and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. The RGD peptide may be linear. The RGD peptide may be cyclic. An RGD peptide may include a D-amino acid. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides. For example, the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide.

[0100] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0101] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0102] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’- fluoro-modified pyrimidine, provided there are not three 2’ -fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’ -fluoro-modified pyrimidine; all purines of the sense strand comprises 2’ -O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’ -fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides and unmodified deoxy ribonucleotides.

[0103] In some embodiments, position nine of the sense strand comprises a 2’ -fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’ -O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’ -fluoro- modified purine, provided there are not three 2’ -fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides andunmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’- fluoro-modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro-modified pyrimidines in a row.

[0104] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0105] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methylmodified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro- modified nucleotides and unmodified deoxyribonucleotide.

[0106] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’ -end group may be or include a 5 ’ -end phosphorothioate, 5 ’ -end phosphorodithioate, 5 ’ -end vinylphosphonate (5’-VP), 5 ’-end methylphosphonate, 5 ’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans- vinylphosphonate or cis-vinylphosphonate. The 5 ’-end group may include an extra 5’ phosphate. A combination of 5 ’-end groups may be used.

[0107] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy -C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used.

[0108] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans- vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5 ’-vinylphosphonate 2’-O-methyl Uridine

[0109] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0110] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.1) Hydrophobic moieties

[0111] In some embodiments, 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.

[0112] In some embodiments, 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. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[0113] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g. , attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide. 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. 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. Preferably, the GalNAc moiety is ETL17. Representative example of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, or ETL28. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrintargeting 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.

[0114] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, 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.

[0115] In some embodiments, 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. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0116] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises anyaspect 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. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0117] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.Table 1: Hydrophobic moiety examples

[0118] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.

[0119] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0120] 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. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.

[0121] 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 mayinclude 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.

[0122] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0123] 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. In some embodiments, Ris 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 theaforementioned numbers of carbons. In some embodiments, 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. In some embodiments, 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.

[0124] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0125] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.2) Sugar moieties

[0126] In some embodiments, 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.

[0127] In some embodiments, 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.

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In someembodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0129] Disclosed herein, in some embodiments, are 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. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2;Q is selected from:C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and Ci-6alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from:-O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, - OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; R3and R4are each independently selected from: -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from: -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selectedfrom any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, - N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2- NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(Q-)O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(Q- )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O )O-, -OP(S)(O)O-, -OP(O)(S )O-, and -OP(OR7)O- In some embodiments, R1is selected from -OP(O)(OR7)O- and -OPCOR7)©-. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and -OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, - OC(O)R7, and -S(O)R7. In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7.In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R4is selected from -OR7- and - OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and - N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6 alky 1)2. -NH(CI-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, and -NH(CI-6 alkyl). In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substitutedwith one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and Ci-3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O- , and -OP(OR7)O-; R2is Ci alkyl substituted with -OH or -OC(O)CH3;R3is -OH or -OC(O)CH3; R4is -OH or -OC(O)CH3; and R5is -NH(O)CH3. In someIn some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphorami date, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0130] Some embodiments include the following, where 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.

[0131] 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.

[0132] 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.

[0133] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and isan 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.

[0134] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0135] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0136] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0137] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0138] Some embodiments include the following, where J is the oligonucleotide: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

[0139] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to theoligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0140] Some embodiments include the following, where 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.

[0141] 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.

[0142] Some embodiments include the following, where J is the oligonucleotide: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 tothe 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.

[0143] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):Formula IV, orFormula V, or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2. -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, - OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-;each R7is independently selected from: hydrogen, Ci-6 alkyl, C2-6 alkenyl, and C2-e alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0144] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0145] 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.

[0146] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0147] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0148] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0149] 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 comprisesone 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.

[0150] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0151] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 ’ or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instancescomprises 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.

[0152] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[0153] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0154] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0155] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphor othioate linking to the oligonucleotide.

[0156] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more 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.

[0157] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0158] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3’ or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0159] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0160] 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.

[0161] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0162] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one ormore 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.

[0163] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0164] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” 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.

[0165] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:

[0166] The structures in this compound attached to the oligonucleotide (J) in some instances are referred to as GLS-5 and GLS-15 and are examples of GalNAc moieties. 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.

[0167] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0168] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Olix GalNAc,” 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.

[0169] Provided herein are sugar moieties comprising the following structure, where J and J’ is an oligonucleotide or a GalNAc moiety:

[0170] 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.

[0171] Provided herein are sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety:

[0172] 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.

[0173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker: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.

[0174] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[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.

[0175] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphatesor 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.

[0176] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0177] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Arbutus,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.3) siRNA modification patterns

[0178] In some embodiments, 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:5 '-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-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. In some embodiments, the sense strand comprises modification pattern 2S: 5'- nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modificationpattern 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. In some embodiments, the sense strand comprises modification pattern 5S: 5'- nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-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. In some embodiments, the sense strand comprises modification pattern 6S: 5'-nnnnnnnNfNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 7S: 5'- nnrmrmnNfNfNfNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 8S: 5'-nnnnnnNfnNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 9S: 5'- nnnnnnNfnNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern IOS: 5'-nrmnrmNfNfNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 1 IS: 5'-nnnrmnNfNfNfNfNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 12S: 5'-nnnnnNfnnNfnNfnnnnnnnnsnsn- 3', wherein “Nf’is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 13S: 5'-nnnnnNfnnNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 14S: 5'-nnnnnNfnNfNfnnnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 15S: 5'-nnnnnNfnNfNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 16S: 5'- nnnnnNfnNfNfNfNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 17S: 5NinnnnNlNfnNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 18S: 5'-nnnnnNlNfnNfnNfnnnnnnnnsnsn-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. In some embodiments,the sense strand comprises modification pattern 19S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 20S: 5'-nnnnnNfNfNfNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 21 S: 5'- nnrmnNfNfNfNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 22S: 5'-nnnnnNfNfNfNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 23S: 5'-nnnnNfnnnNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 24S: 5NinnnNfnnnNlNfnnnnnnnnnsnsn- 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. In some embodiments, the sense strand comprises modification pattern 25S: 5NinnnNfnnNlNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 26S: 5'-nnnnNfnnNfNfnNfnnnnnnnnsnsn- 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. In some embodiments, the sense strand comprises modification pattern 27S: 5'-nnnnNfnnNfNfNfNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 28S: 5NinnnNfnNfnNfnnnnnnnnnnsnsn- 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. In some embodiments, the sense strand comprises modification pattern 29S: 5NinnnNfnNfnNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 30S: 5'-nnnnNfnNfnNlNfnnnnnnnnnsnsn- 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. In some embodiments, the sense strand comprises modification pattern 3 IS: 5'-nnnnNfnNfNfNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 32S: 5NinnnNlNfnnNfnnnnnnnnnnsnsn- 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. In some embodiments, the sense strand comprises modification pattern 33S: 5NinnnNlNfnnNfnNfnnnnnnnnsnsn-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. In someembodiments, the sense strand comprises modification pattern 34S: 5'-nnnnNfNfnnNfNfnnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 35S: 5'-nnnnNfNfnNfNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 36S: 5'- nnrmNfNfnNfNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 37S: 5'-nrmnNfNfNfNfNfnrmnnnnnnnsnsn-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. In some embodiments, 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. In some embodiments, the sense strand comprises modification pattern 39S: 5'-nnnnnnnnNfnNfnnnnnnnnsnsn-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. In some embodiments, 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. In some embodiments, the sense strand comprises modification pattern 41 S: 5'- snnnnnNfnNlNfnnnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 42S: 5'- snnnnNfnNfnNfnnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 43 S: 5'- snnnnnnNfnNfnNfnnnnnnnnsnsn- 3', wherein “Nf’ is a 2’ -fluoro-modified nucleoside, “n” is a2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 44S: 5'- snnnnNfnNlNfdNNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 45S: 5'- snnnnnNfnnNfnNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 46S: 5'- snrmnNfNfNfNfNfnrmnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 47S: 5'- snnnnNfnnNfNfNfNfnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 48S: 5'- snnnnNfNfnnNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 49S: 5'- snnnnNfnNfnNfNfnnnnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 50S: 5'- snnnnnNfNfNfNfnNfnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 5 IS: 5'- snnnnnNfnnNfNfnnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 52S: 5'- snnnnnnNfNfNINfnnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 53 S: 5'- snnnnNfnnnNfNfnnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 54S: 5'- snnnnnNfNfnNfNfnnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 55 S: 5'- snnnnNfnNfNfdNnNfnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 56S: 5'- snnnnNfnnnNfnNfnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 57S: 5'- snnnnNINfnnNfnnnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 58S: 5'- snnnnNfnnNINfnNfnnnnnnnnsnsn -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. In some embodiments, the sense strand comprises modification pattern 59S: 5’- snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-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- methoxy ethyl modified nucleoside, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 60S: 5’- snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-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. In some embodiments, the nm is a 2’-O-methoxyethyl modified thymine. In some embodiments, the sense strand comprises modification pattern 61 S: 5’- snnnNmnNfNfNfNfnnnnNmnnnnnsnsn-3'. wherein “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, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 62S: 5’- snnnnnmNfNfNfNfnnnnmnnnnnnsnsn-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. In some embodiments, the sense strand comprises modification pattern 63S: 5’- snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-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. In some embodiments, the nm is a2’-O-methoxyethyl modified thymine. In some embodiments, the sense strand comprises modification pattern 64S: 5’- snnnnnmNfNfNfNfnnnnnmnnnnnsnsn-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. In some embodiments, the nm is a 2’-O-methoxyethyl modified thymine. In some embodiments, the nm is a2’-O-methoxyethyl modified thymine. In some embodiments, the nm is a2’-O- methoxy ethyl modified thymine. In some embodiments, the sense strand comprises modification pattern 65S: 5’- snrmnrnnNfNfNfNfnnmnnnnnnnnsnsn- 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. In some embodiments, 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’- snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-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- methoxy ethyl modified nucleoside, and N comprises one or more nucleosides. In some embodiments, the nm is a 2’-O-methoxyethyl modified thymine. In some embodiments, the nm is a 2’-O-methoxyethyl modified thymine.

[0179] In some embodiments, 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:5 '-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3'. wherein “Nf ’ is a2’-fhroro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'- nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a2’-O- methyl modified nucleoside, and “s” is a phosphate or phosphorothioate linkage. In some embodiments, 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. In some embodiments, the antisense strand comprises modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3', wherein “Nf’ is a 2’ -fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphate orphosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 5 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-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. In some embodiments, the antisense strand comprises modification pattern 6AS:5'-nsnsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-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. In some embodiments, the antisense strand comprises modification pattern 7AS:5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the antisense strand comprises modification patternI I AS:5'-nsNfsnNfnnNfnnNfnNfnNfnnnnnsnsn-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. In some embodiments, the antisense strand comprises modification pattern 12AS:5’-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-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. In some embodiments, the antisense strand comprises modification pattern13AS:5'-nsNfsnnnNfnNfnNfnNfnNfnnnnnsnsn-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. In some embodiments, 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. In some embodiments, the antisense strand comprises modification pattern 15AS:5’-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-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. In some embodiments, the antisense strand comprises modification pattern 16AS:5’- nsNfsnNfnNfnNfnNfnNfnNfnNfnnnsnsn-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.

[0180] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and anantisense 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. In some embodiments, 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. 14AS, 15AS or 16AS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 or16AS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 or16AS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 or16AS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0181] In some embodiments, 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. In some embodiments, the sense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S,15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S,35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S,55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S. In some embodiments, the sense strand comprises modification pattern 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S .

[0182] In some embodiments, 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. In some embodiments, 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 2AS. In some embodiments, 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 3 AS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 66Sand the antisense strand comprises modification pattern HAS. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the sense strand comprises modification pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, MAS, MAS or 16AS. In some embodiments, the antisense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, MAS or 16AS . In some embodiments, 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. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

[0183] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines.Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0184] In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modifiedpurines. In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines.

[0185] In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines.

[0186] In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’ -O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’ -fluoro modified purines.

[0187] In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ - fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines,and all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-meihyl modified purines. In some embodiments, 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.

[0188] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’flouro-modified pyrimidine, provided there are never three 2’ -fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, 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.

[0189] In some embodiments, position nine of the sense strand comprises a 2’ -fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’ -O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’flouro- modified purine, provided there are never three 2’ -fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’ -fluoro-modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’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.

[0190] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2 ’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodifieddeoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotides.

[0191] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’flouro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’flouro- modified nucleotides and unmodified deoxyribonucleotides.

[0192] In some embodiments, 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. 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, 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. In some embodiments, 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.

[0193] In some embodiments, 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. 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, 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.

[0194] 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, 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 Table16, 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 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 Table17. 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, 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. 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, or an siRNA thereofhaving 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 Table22, 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 Table23. 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, 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.

[0195] 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, 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. 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. 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. 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. In some embodiments, the antisense strand sequence comprises or consists of an antisense strand sequence of any one of the siRNAs disclosed inTable 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. 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. 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. 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. 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. 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. 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.

[0196] In some embodiments, 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. For example, a sense strand may omit a 3’ AUU of a sense strand sequence in any of Tables 21-25. 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. In some embodiments, 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. 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 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.

[0197] A sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 21. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 21. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 21. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 21. In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 21 omitting an AUU sequence. In some embodiments, 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.

[0198] A sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 22. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 22. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 22. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 22. In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 22 omitting an AUU sequence. In some embodiments, 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.

[0199] A sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 23. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 23. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 23. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 23. In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 23 omitting an AUU sequence. In some embodiments, 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.

[0200] A sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 24. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1 -18 of a sense strand in Table 24. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 24. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 24. In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 24 omitting an AUU sequence. In some embodiments, the sense strand can be a nucleoside sequence that is at least90% identical to a nucleoside sequence in Table 24 and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.

[0201] A sense strand sequence may omit a 3’ AUU of a sense strand sequence in Table 25. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand in Table 25. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand in Table 25. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table 25. In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table 25 omitting an AUU sequence. In some embodiments, 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.

[0202] In some embodiments, the antisense strand includes a nucleoside sequence of an antisense strand in any of Tables 21-25 and omits a U or UU. For example, an antisense strand may omit a 5’ U and a 3’ UU of an antisense strand sequence in any of Tables 21-25. 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. In some embodiments, 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. 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 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.

[0203] An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 21. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 21. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 21. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 21. In some embodiments, 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. In some embodiments, 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.

[0204] An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 22. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 22. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 22. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 22. In some embodiments, 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. In some embodiments, the antisensestrand 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.

[0205] An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 23. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 1- 18 of an antisense strand in Table 23. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 23. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 23. In some embodiments, 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. In some embodiments, 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.

[0206] An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 24. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 24. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 24. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 24. In some embodiments, 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. In some embodiments, 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.

[0207] An antisense strand sequence may omit a 5’ U and 3’ UU of an antisense strand sequence in Table 25. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 1 - 18 of an antisense strand in Table 25. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table 25. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table 25. In some embodiments, 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. In some embodiments, 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.

[0208] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 27. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 27. In some embodiments, 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. In some embodiments, 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. In some embodiments, the sense strand or antisensesequence 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.

[0209] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 31. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 31. In some embodiments, 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. In some embodiments, 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. 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 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.

[0210] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 34. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 34. In some embodiments, 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. In some embodiments, 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. 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 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.

[0211] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 37. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 37. In some embodiments, 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. In some embodiments, 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. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strandsequence 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.

[0212] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 10981-11000. In some embodiments, 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. 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, 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.

[0213] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11001-11020. In some embodiments, 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. 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, 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.

[0214] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11021-11090. In some embodiments, 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. 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, 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 asense 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.

[0215] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11091-11115. In some embodiments, 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. 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, 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.

[0216] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11116-11140. In some embodiments, 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. 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, 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.

[0217] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11141-11252. In some embodiments, 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. 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 thereofhaving 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.

[0218] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11254-11263. In some embodiments, 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. 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, 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.

[0219] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11264-11273. In some embodiments, 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. 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, 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.

[0220] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11334-11343. In some embodiments, 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% identicalto any one of SEQ ID NOs: 11334-11343. 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, 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.

[0221] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11344-11345. In some embodiments, 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. 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, 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.

[0222] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 11414-11443. In some embodiments, 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. 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, 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.

[0223] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 11444-11468. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 11444-11468, atleast 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. 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, 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.4) ASO modification patterns

[0224] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of S0S2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-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. In some embodiments, 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. 14AS, 15AS or 16AS.D. F ormulations

[0225] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0226] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. In some embodiments, the composition is formulated for ocular delivery.E. Kits

[0227] Described herein, in some embodiments, are kits. The kit may include an oligonucleotide such as an siRNA described herein. The oligonucleotide may be conjugated to a lipid moiety or to asugar 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.II. METHODS AND USES

[0228] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

[0229] 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.

[0230] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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 thedisorder. 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.

[0235] In some embodiments, the administration is systemic. In some embodiments, the administration is by parenteral administration. In some embodiments, the administration is local (e.g., to a particular organ or tissue). In some embodiments, the administration is by inhalation. In some embodiments, the administration is topical. In some embodiments, the administration is by infusion. In some embodiments, the administration is by injection. In some embodiments, the administration is intravenous (e.g., by intravenous injection or infusion). In some embodiments, the administration is subcutaneous (e.g., by subcutaneous injection). In some embodiments, the administration is intraperitoneal. In some embodiments, the administration is intraparenchymal. In some embodiments, the administration is intramuscular (e.g., by intramuscular injection). In some embodiments, the administration may be to an eye tissue (e.g., by intravitreal, intracameral or subconjunctival injection, or by topical administration to the eye). In some embodiments, the administration may be to a central nervous system tissue (e.g., brain or spinal cord or spinal canal). In some embodiments, the administration is intracerebroventricular or intrathecal (e.g., by intrathecal injection or infusion). In some embodiments, the administration may be to joint tissue (e.g., by intra-articular injection). In some embodiments, the administration may be to airway or lung tissue (e.g., by intranasal, intratracheal or inhaled administration). In some embodiments, the administration may be to skin or connective tissue (e.g., by topical administration or injection to the skin). In one another embodiment, the pharmaceutical composition is for intraocular administration. In one another embodiment, 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. As a still further option, 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.

[0236] The pharmaceutical 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.A. Disorders

[0237] 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. In some embodiments, 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, diabeticretinopathy, non-alcoholic fatty liver disease, fibrotic liver disease, liver fibrosis, cirrhosis, or hair loss disorder. In some embodiments, the disord...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising an siRNA that targets SOS2 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.

2. The composition of claim 1, wherein 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.

3. A 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.

4. The composition of claim 3, wherein the blood urate measurement is decreased by about 10% or more, as compared to prior to administration.

5. A 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.

6. The composition of claim 5, wherein 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.

7. 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 strand comprises a sequence selected from any one of SEQ ID NOS: 11444-11468.

8. The composition of claim 7, wherein 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.

9. A 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.

10. The composition of claim 9, wherein 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.

11. A 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.

12. The composition of claim 11, wherein 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.

13. A 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.

14. A 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, 61 S, 62S, 63S, 64S, 65S, or 66S.

15. A 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 isindependently 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, I3AS. 14AS, 15AS, or 16AS.

16. The composition of any one of claims 13-15, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.

17. The composition of claim 16, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

18. The composition of claim 16, wherein the lipid comprises a 5’ hydrophobic moiety comprising any one of the following structures:, wherein the 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.

19. The composition of claim 18, wherein the lipid comprises20. The composition of any one of claims 1-14, wherein the oligonucleotide comprises an N- acetylgalactosamine (GalNAc) ligand, an arginine-glycine-aspartic acid (RGD) peptide, or a cholesterol ligand.

21. The composition of any one of claims 1-14, wherein the oligonucleotide comprises a GalNAc ligand.

22. The composition of claim 21, wherein the GalNAc ligand comprises the structure:wherein J is the oligonucleotide.

23. A method of treating 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 in a subject in need thereof comprising administering to the subject a composition according to any one of claims 1-22.

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