Treatment of GPAM related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets GPAM. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with GPAM gene mutations that include providing an oligonucleotide that targets GPAM in a subject. Some examples of diseases that may be treated include liver diseases or cardiometabolic diseases.

Description

TREATMENT OF GPAM RELATED DISEASES AND DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 612,939, filed December 20, 2023, and U.S. Provisional Application No. 63 / 694,129, filed September 12, 2024, all of which applications are incorporated herein by reference in their entirety.BACKGROUND

[0002] Metabolic disorders such as liver disorders and cardiovascular disorders are widely abundant, and may affect a wide variety of people. Improved therapeutics are needed for treating these disorders.SUMMARY

[0003] In certain aspects, disclosed herein is a composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount improves circulating cholesterol, apolipoprotein B, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase in a subj ect, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69 AS. In some embodiments, the cholesterol comprises total cholesterol, low density lipoprotein cholesterol, or non-high density lipoprotein cholesterol. In some embodiments, the cholesterol is improved by about 10% or more, as compared to prior to administration. In certain aspects, disclosed herein is a composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount improves a liver fibrosis score, non-alcoholic fatty liver disease (NAFLD) activity score, or liver fat percentage in a subject, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61 S, 55S, 56AS, 9 AS, 57AS, 30AS, 58AS, 68AS, and 69AS. In some embodiments, the improvement is by about 10% or more, as compared to prior to administration. In certain aspects, disclosed herein is a composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount decreases a use of statin (HMG Co A reductase inhibitor) medication, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69AS. In some embodiments, the decrease is by about 10% or more, as compared to prior to administration. In certain aspects, disclosed herein is a composition comprising an siRNA that targets GPAM and when administered to a subj ect in an effective amount improves a measurement that reflects a phenotype of esophageal varices, portal hypertension, NAFLD (or MASLD), NASH (or MASH), alcoholic liver disease, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, hyperlipidemia, ischemic heart disease, or coronary heart disease in a subject, wherein the siRNA comprises a modification patternselected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9 AS, 57AS, 30AS, 58AS, 68AS, and 69AS. In some embodiments, the improvementis by about 10% or more, as compared to prior to administration. In certain aspects, disclosed herein is a composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount increases circulating ketone bodies in a subject wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9 AS, 57AS, 30AS, 58AS, 68AS, and 69 AS. In some embodiments, the increase is by about 10% or more, as compared to prior to administration. In some embodiments, the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety, an N-acetylglucosamine (GlcNAc) moiety, or a mannose moiety, attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises a GalNAc moiety. In some embodiments, the oligonucleotide further comprises, whereinJ comprises the oligonucleotide, and wherein J comprises an optional phosphate or phosphorothioate linking to the oligonucleotide. In some embodiments, the siRNA comprises a sense strand and an antisense strand. In some embodiments, the sense strand comprises a sequence comprising at least 19 nucleosides of any one of SEQ ID NO: 1-6354, 13082-13402, 13951-14078, or 14285-14296, or 14337-14339. In some embodiments, the sense strand comprises a sequence comprising at least 15, 16, 17, 18, or 19 consecutive nucleosides of any one of SEQ ID NO: 1-6354, 13082-13402, 13951- 14078, or 14285-14296, or 14337-14339. In some embodiments, the antisense strand comprises a sequence comprising at least 19 nucleosides of any one of SEQ ID NO: 6355-12708, 13403-13723, 14079-14206, 14297-14307, or 14340-14342. In some embodiments, the antisense strand comprises a sequence comprising at least 15, 16, 17, 18, 19 consecutive nucleosides of any one of SEQ ID NO: 6355-12708, 13403-13723, 14079-14206, 14297-14307, or 14340-14342. In certain aspects, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, eachstrand is independently about 12-30 nucleosides in length, wherein the siRNA comprises sense sequence comprising any one of SEQ ID NO: 13780-13840, 13914-13937, 14254-14255, 14308- 14319, or 14331-14333 or an antisense sequence comprising any one of SEQ ID NO: 13841 -13913, 13938-13950, 14207-14253, 14256-14276, 14277-14284, 14320-14330, or 14334-14336. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, disclosed herein is a method of treating a subject having liver disease, comprising administering an effective amount of the composition disclosed herein to the subject. In some embodiments, the liver disease comprises NAFLD (or MASLD), NASH (or MASH), alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma. In some embodiments, disclosed herein is a method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition disclosed herein to the subject. In some embodiments, the cardiometabolic disease comprises hyperlipidemia, ischemic heart disease, or coronary heart disease. In certain aspect, disclosed herein is a method of treating a subject having liver disease, comprising administering an effective amount of the composition as described above to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist. In some embodiments, the liver disease comprises NAFLD (or MASLD), NASH (or MASH), alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma. In some embodiments, the GLP-1 receptor agonist comprises exenatide, lixisenatide, liraglutide, dulaglutide, tirzepatide, dulaglutide, semaglutide or a combination thereof. In certain aspects, disclosed herein is a method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition as described above to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist. In some embodiments, the cardiometabolic disease comprises hyperlipidemia, ischemic heart disease, or coronary heart disease In some embodiments, the GLP-1 receptor agonist comprises exenatide, lixisenatide, liraglutide, dulaglutide, tirzepatide, dulaglutide, semaglutide or a combination thereof. In certain aspect, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of GPAM in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, 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 siRNA comprises sense sequence comprising any one of SEQ ID NO: 13780-13840, 13914-13937, 14254-14255, 14308-14319, or 14331-14333, or an antisense sequence comprising any one of SEQ ID NO: 13841-13913, 13938-13950, 14207-14253, 14256- 14276, 14277-14284, 14320-14330, or 14334-14336. In certain aspects, disclosed herein is a method of treating a subject having liver disease, the method comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, GIP receptor antagonist, glucagon receptor agonist, amylin receptor agonist, apelin receptor agonist, peptide YY receptor agonist, calcitonin receptor agonist, growth differentiation factor- 15(GDF15) analogue, fibroblast growth factor 21 (FGF21) analog, fibroblast growth factor 21 (FGF19) analog, peroxisome proliferator-activated receptors (PPAR) agonist, thyroid hormone receptor-β agonist, FXR agonist, antagonist or modulator of inhibin βE (INHBE) / activin E expression or function, antagonist or modulator of activin receptor-like kinase 7 (ALK7) expression or function, antagonist or modulator of diacylglycerol acyltransferase (DGAT) or acetyl-CoA carboxylase (ACC) expression or function, antagonist or modulator of patatin-like phospholipase domain- containing protein 3 (PNPLA3) expression or function, antagonist or modulator of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) expression or function, antagonist or modulator of mitochondrial amidoxime-reducing component 1 (MTARC1) expression or function, or a combination thereof. In certain aspects, disclosed herein is a method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, glucosedependent insulinotropic polypeptide (GIP) receptor agonist, GIP receptor antagonist, glucagon receptor agonist, amylin receptor agonist, apelin receptor agonist, peptide YY receptor agonist, calcitonin receptor agonist, growth differentiation factor- 15 (GDF15) analogue, fibroblast growth factor 21 (FGF21) analog, fibroblast growth factor 21 (FGF19) analog, peroxisome proliferator- activated receptors (PPAR) agonist, thyroid hormone receptor-β agonist, FXR agonist, antagonist or modulator of inhibin βE (INHBE) / activinE expression or function, antagonist or modulator of activin receptor-like kinase 7 (ALK7) expression or function, antagonist or modulator of diacylglycerol acyltransferase (DGAT) or acetyl-CoA carboxylase (ACC) expression or function, antagonist or modulator of patatin-like phospholipase domain- containing protein 3 (PNPLA3) expression or function, antagonist or modulator of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) expression or function, antagonist or modulator of mitochondrial amidoxime-reducing component 1 (MTARC1) expression or function, or a combination thereof.DETAILED DESCRIPTION

[0004] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GW AS) detects associations between genetic variants and traits in a population sample, and this improves understanding of the biology of disease and provides evidence of applicable treatments. A GWAS generally utilizes 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 considered associated with disease. Association statistics used in a GWAS include 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 theincreased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GW AS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0005] Functional annotation of variants and / or wet lab experimentation is used to identify a causal genetic variant identified via GWAS, and in many cases leads to 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) allows 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.

[0006] Identification of such gene-disease associations has provided insights into disease biology and is 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 is exogenously ‘programmed’ into replicating the observation from human genetics. There are several options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These 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 depends on factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, fat or liver) and a relevant indication.

[0007] The GPAM (also known as GPAT or GPAT1) gene is located on chromosome 10, and encodes glycerol-3-phosphate acyltransferase, mitochondrial (GPAM). GPAM may include 828 amino acids and have a mass of about 94 kDa. GPAM may be expressed in liver, adipose, adrenal, thyroid, heart, gall bladder, brain, salivary gland, and testis cells. GPAM may be intracellular. GPAM may exist as two different enzymatic forms, in the mitochondria or in the endoplasmic reticulum. GPAM may catalyze the initial and committing step in glycerolipid biosynthesis and can play a significant role in the regulation of cellular triacylglycerol and phospholipid levels. The mitochondrial enzyme GPAM may preferentially use saturated fatty acids as a substrate for the synthesis of glycerolipids. GPAM may catalyze the first step in this metabolic pathway. GPAM may interact with APP, SREBF1, AGP ATI, AGPAT2, AGPAT3, AGPAT4, AGPAT5, AGPAT6, AGPAT9, GPD1, or MBOAT2. An example of an 828 amino acid sequence, and further description of GPAM is included at uniprot.org under accession no. Q9HCL2 (last modified May 25, 2022). A potential alternatively spliced isoform of GPAM producing a 710 amino acid sequence is included at uniprot.org under accession no. Q5VW52 (last modified Dec. 07, 2004).

[0008] Here it is shown that genetic loss-of-function GPAM variants result in protective blood ketone associations, liver disease-related associations, liver function associations, and blood lipid associations. Therefore, inhibition of GPAM may serve as a therapeutic for treatment of liver orcardiometabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD, also known as metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis (MASH)), alcoholic liver disease, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, hyperlipidemia, ischemic heart disease, or coronary heart disease. The GPAM inhibition may result in an improved liver function, cardiovascular function, and metabolic phenotypes including favorable liver fat percentage, liver fibrosis score, NAFLD activity score, liver enzyme function test, serum metabolite test, or serum lipid panel test.

[0009] Disclosed herein are compositions comprising an oligonucleotide that targets GPAM. Where inhibition or targeting of GPAM is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a GPAM protein or GPAM RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the GPAM gene using an oligonucleotide described herein, the GPAM protein may be inhibited or targeted as a result of there being less production of the GPAM protein by translation of the GPAM RNA; or a GPAM protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a GPAM RNA and reduces production of the GPAM protein from the GPAM RNA. Thus, targeting GPAM may refer to binding a GPAM RNA and reducing GPAM RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Administration of the oligonucleotide to a subject may improve (e.g., decrease or increase) a liver fat percentage, liver fibrosis score, NAFLD activity score, blood alanine aminotransferase (ALT), blood aspartate aminotransferase (AST), blood alkaline phosphatase (ALP), blood bilirubin, low-density lipoprotein (LDL), total cholesterol, non-HDL cholesterol, or apolipoprotein B (APOB) measurement, or a combination thereof in the subject. Also provided herein are methods of treating a liver or cardiometabolic disorder by providing an oligonucleotide that targets GPAM to a subject in need thereof.I. COMPOSITIONS

[0010] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets GPAM. In some embodiments, the composition consists of an oligonucleotide that targets GPAM. In some embodiments, the oligonucleotide reduces GPAM mRNA expression in the subject. In some embodiments, the oligonucleotide reduces GPAM 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. In some embodiments, thesiRNA comprises a modification patern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 157S, 158S, 159S, 160S, 161S, 162S, 163S, 164S, 68AS, 69AS, 70AS, 71AS, and 72AS. In some embodiments, the siRNA comprises sense sequence comprising any one of SEQ ID NO: 13780-13840, 13914-13937, 14254-14255, 14308-14319, or 14331-14333or an antisense sequence comprising any one of SEQ ID NO: 13841-13913, 13938-13950, 14207-14253, 14256- 14276, 14277-14284, 14320-14330, or 14334-14336.

[0011] Some embodiments include a composition comprising an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases GPAM mRNA or protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases GPAM mRNA levels in a cell or tissue. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is fat tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is an adipocyte. In some embodiments, the GPAM 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 GPAM mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the GPAM 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, or about 100%, as compared to prior to administration. In some embodiments, the GPAM 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 GPAM mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the GPAM 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%, or no more than about 90%, as compared to prior to administration. In some embodiments, the GPAM 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.

[0012] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases GPAM protein levels in a cell, fluid or tissue. In some embodiments, the composition decreases GPAM protein levels in a cell or tissue. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is fat tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is an adipocyte. In some embodiments, the GPAM 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 GPAM protan levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the GPAM 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 GPAM 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 GPAM protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the GPAM 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%, or no more than about 90%, as compared to prior to administration. In some embodiments, the GPAM 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.

[0013] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount improves a liver disease phenotype. The liver disease may include non-alcoholic fatty liver disease (NAFLD, also known as metabolic dysfunction- associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis (MASH)), alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma. In some embodiments, the liver disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the liver disease phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the liver disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the liver disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the liver disease phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the liver disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the liver disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0014] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount improves a cardiometabolic disease phenotype. The cardiometabolic disease may include hyperlipidemia, ischemic heart disease, or coronary heart disease. In some embodiments, the cardiometabolic disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by about 10% or more, ascompared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the cardiometabolic disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0015] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subj ect in an effective amount improves a protective phenotype against a liver disease in the subject. The liver disease may include non-alcoholic fatty liver disease (NAFLD, also known as metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis (MASH)), alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma. In some embodiments, the protective phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 10% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0016] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount improves a protective phenotype against a cardiometabolic disease in the subject. The cardiometabolic disease may include hyperlipidemia, ischemic heart disease, or coronary heart disease. In some embodiments, the protective phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 10% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0017] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating cholesterol in the subject. The circulating cholesterol may include total cholesterol or non-high density lipoprotein (HDL) cholesterol. The circulating cholesterol may include total cholesterol. The circulating cholesterol may include non-HDL cholesterol. In some embodiments, the circulating cholesterol is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. Insome embodiments, the circulating cholesterol is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating cholesterol 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating cholesterol is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to priorto administration In some embodiments, the circulating cholesterol is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating cholesterol is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating cholesterol 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 100%, or by a range defined by any of the two aforementioned percentages.

[0018] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating low density lipoproteins (LDL) in the subject. In some embodiments, the circulating LDL 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 circulating LDL is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating LDL 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating LDL 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 circulating LDL is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating LDL is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating LDL 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 100%, or by a range defined by any of the two aforementioned percentages.

[0019] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating apolipoprotein B (APOB) in the subject. In some embodiments, the circulating APOB 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 circulating APOB is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating APOB 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating APOB 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 circulating APOB is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating APOB is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating APOB 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 100%, or by a range defined by any of the two aforementioned percentages.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating alanine aminotransferase (ALT) in the subject. In some embodiments, the circulating ALT 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 circulating ALT is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating ALT 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating ALT 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 circulating ALT is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating ALT is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating ALT 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 100%, or by a range defined by any of the two aforementioned percentages.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating aspartate aminotransferase (AST) in the subject. In some embodiments, the circulating AST 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 circulating AST is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating AST 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating AST 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 someembodiments, the circulating AST is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating AST is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating AST 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 100%, or by a range defined by any of the two aforementioned percentages.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating alkaline phosphatase (ALP) in the subject. In some embodiments, the circulating ALP 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 circulating ALP is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating ALP 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating ALP 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 circulating ALP is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating ALP is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating ALP 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 100%, or by a range defined by any of the two aforementioned percentages.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases circulating bilirubin in the subject. In some embodiments, the circulating bilirubin 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 circulating bilirubin is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating bilirubin 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, or about 100%, as compared to prior to administration. In some embodiments, the circulating bilirubin 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 circulating bilirubin is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating bilirubin 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 thanabout 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the circulating bilirubin 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 100%, or by a range defined by any of the two aforementioned percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount improves a nonalcoholic fatty liver disease (NAFLD) activity score in the subject. In some embodiments, the NAFLD activity score is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by about 10% or more, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the NAFLD activity score is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases a liver fat percentage in the subject. In some embodiments, the liver fat percentage 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 fat percentage is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the liver fat percentage 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, or about 100%, as compared to prior to administration. In some embodiments, the liver fat percentage 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 fat percentage is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the liver fat percentage is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the liver fat percentage 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 100%, or by a range defined by any of the two aforementioned percentages.

[0026] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subj ect in an effective amount improves a liver fibrosis score in the subj ect. In some embodiments, the liver fibrosis score is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by about 10% or more, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the liver fibrosis score is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0027] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount decreases a use of an HGM Co A reductase inhibitor (e.g. , a statin) medication in the subject. In some embodiments, the use of statin medications 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 use of statin medications is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the use of statin medications 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, or about 100%, as compared to prior to administration. In some embodiments, the use of statin medications 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 use of statin medications is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the use of statin medications is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the use of statin medications 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 100%, or by a range defined by any of the two aforementioned percentages.

[0028] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount increases circulating ketone bodies in the subject. In some embodiments, the circulating ketone body 3 -hydroxy butyrate 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 circulating ketone body 3-hydroxy butyrate is increased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating ketone body 3- hydroxybutyrate 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 circulating ketone body 3-hydroxybutyrate 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 circulating ketone body 3-hydroxybutyrate 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 circulating ketone body 3-hydroxybutyrate is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating ketone body 3-hydroxybutyrate 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 circulating ketone body 3-hydroxybutyrate 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 circulating ketone body 3-hydroxybutyrate 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 arange defined by any of the two aforementioned percentages.

[0029] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount increases circulating ketone bodies in the subject. In some embodiments, the circulating ketone body acetoacetate 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 circulating ketone body acetoacetate is increased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating ketone body acetoacetate 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 circulating ketone body acetoacetate 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 circulating ketone body acetoacetate 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 circulating ketone body acetoacetate is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating ketone body acetoacetate 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 circulating ketone body acetoacetate 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 circulating ketone body acetoacetate 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.

[0030] In some embodiments, the composition comprises an oligonucleotide that targets GPAM and when administered to a subject in an effective amount increases circulating ketone bodies in the subject. In some embodiments, the circulating ketone body acetone 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 circulating ketone body acetone is increased by about 10% or more, as compared to prior to administration. In some embodiments, the circulating ketone body acetone 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 circulating ketone body acetone 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 circulating ketone body acetone 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 circulating ketone body acetone is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the circulating ketone body acetone 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 circulating ketone body acetone 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 about800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the circulating ketone body acetone 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.A.siRNAs

[0031] In some embodiments, the composition comprises an oligonucleotide that targets GPAM, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets GPAM, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human GPAM mRNA sequence such as SEQ ID NO: 12867. 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: 12867. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 12867. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 12867. Any of the aforementioned siRNAs may include a sense strand of SEQ ID NO: 12867, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of SEQ ID NO: 12867, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand of the composition 5’ -(N)0-7(NB)(N)0-7-3’ and an antisense strand of composition 5’-(N)0-7(NA)(N)0-7-3’. Where (N)0-7are independently nucleic acid stretches of 0 to 7 nucleotides, (NB) and (NA) contain at least 15 contiguous nucleotides from Table 8 and contain no cyclic ribose nucleotides with 2’ hydroxyl groups. The sense and antisense strand have 1-5 phosphorothioate inter -nucleotide linkages and either the sense or antisense strand has a targeting ligand attached to the 5’ or 3’ end. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand composition. The targeting ligand may be a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal-6]s[Gal- 6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL 18, ETL19, ETL 20, ETL21, ETL22 or ETL28. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha- v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0035] 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.

[0036] 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.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human GPAM 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 GPAM mRNA.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate GPAM 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 a 25mer in a non-human primate GPAM mRNA.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human GPAM 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 GPAM 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 GPAM mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human GPAM 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 GPAM 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 GPAM 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 GPAM 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 GPAM 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 GPAM 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 GPAM mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.

[0040] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human GPAM mRNA target site that does not harbor an SNP, with aminor 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%.

[0041] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-6354. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1-6354, at least 80% identical to any one of SEQ ID NOs: 1-6354, at least 85% identical to of any one of SEQ ID NOs: 1-6354, at least 90% identical to any one of SEQ ID NOsl-6354, or at least 95% identical to any one of SEQ ID NOs: 1-6354. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-6354, 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: 1-6354, 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: 1-6354. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1-6354. The sense strand may comprise an overhang. 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. The sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targetingligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand.

[0042] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 6355-12708. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 6355- 12708, at least 80% identical to any one of SEQ ID NOs: 6355-12708, at least 85% identical to of any one of SEQ ID NOs: 6355-12708, at least 90% identical to any one of SEQ ID NOs: 6355-12708, or at least 95% identical to any one of SEQ ID NOs: 6355-12708. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6355-12708, 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: 6355-12708, 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: 6355-12708. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand.

[0043] Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1-6354. Any of the aforementioned siRNAs may includean antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 6355-12708. In any of SEQ ID NOs: 1-6354, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 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: 1-6354 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: 1-6354 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-6354 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1 -6354 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to aT or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-6354 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-6354 is modified to a G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-6354 is modified to a C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-6354 is modified to a C.

[0044] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 13082-13402. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13082-13402, at least 80% identical to any one of SEQ ID NOs: 13082-13402, at least 85% identical to of any one of SEQ ID NOs: 13082-13402, at least 90% identical to any one of SEQ ID NOs: 13082-13402, or at least 95% identical to any one of SEQ ID NOs: 13082-13402. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13082-13402, or an sensestrand 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: 13082-13402, or an sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 13082-13402. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5 ’ to 3 ’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The sense strand may comprise a modification pattern described herein. The sense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NO: 13082-13402. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise a LDL receptor ligand.

[0045] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 13403-13723. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13403- 13723, at least 80% identical to any one of SEQ ID NOs: 13403-13723, at least 85% identical to of any one of SEQ ID NOs: 13403-13723, at least 90% identical to any one of SEQ ID NOs: 13403- 13723, or at least 95% identical to any one of SEQ ID NOs: 13403-13723. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13403- 13723, 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: 13403-13723, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strandsequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 13403-13723. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand.

[0046] Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 13082-13402. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 13403-13723. In any of SEQ ID NOs: 13082-13402, 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: 13082-13402 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: 13082-13402 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: 13082-13402 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: 13082-13402 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: 13082-13402 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: 13082-13402 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: 13082-13402 is modified to an A. In some embodiments, position 1 (from the 5’ end ofany one of SEQ ID NOs: 13082-13402 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 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: 13082-13402 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 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: 13082-13402 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to a C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13082-13402 is modified to a 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: 13082-13402 is modified to a C.

[0047] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 13951-14078. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13951-14078, at least 80% identical to any one of SEQ ID NOs: 13951-14078, at least 85% identical to of any one of SEQ ID NOs: 13951-14078, at least 90% identical to any one of SEQ ID NOsl3951-1407813951- 14078, or at least 95% identical to any one of SEQ ID NOs: 13951-14078. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13951- 14078, 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: 13951-14078, 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: 13951-14078. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. 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 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. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NO: 13951-14078. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand. In any of SEQ ID NOs: 13951-14078, thymine (T) may be replaced with uracil (U).

[0048] 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: 13951-14078 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: 13951-14078 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: 13951-14078 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: 13951-14078 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: 13951-14078 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: 13951-14078 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 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: 13951-14078 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 13951-14078 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 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: 13951-14078 is modified to aT or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 is modified to an G. In some embodiments, position 14 (from the 5’end) of any one of SEQ ID NOs: 13951-14078 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 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: 13951-14078 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 is modified to a C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 13951-14078 is modified to a 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: 13951-14078 is modified to a C.

[0049] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 14079-14206. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 14079- 14206, at least 80% identical to any one of SEQ ID NOs: 14079-14206, at least 85% identical to of any one of SEQ ID NOs: 14079-14206, at least 90% identical to any one of SEQ ID NOs: 14079- 14206, or at least 95% identical to any one of SEQ ID NOs: 14079-14206. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 14079- 14206, 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: 14079-14206, 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: 14079-14206. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein(LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 14079-14206. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 13951-14078. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 14079-14206.

[0050] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 14285-14296 or 14337-14339. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 14285- 14296 or 14337-14339, at least 80% identical to any one of SEQ ID NOs: 14285-14296 or 14337- 14339, at least 85% identical to of any one of SEQ ID NOs: 14285-14296 or 14337-14339, at least 90% identical to any one of SEQ ID NOs: 14285-14296 or 14337-14339, or at least 95% identical to any one of SEQ ID NOs: 14285-14296 or 14337-14339. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 14285-14296 or 14337- 14339, 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: 14285-14296 or 14337-14339, 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: 14285-14296 or 14337-14339. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. 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 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. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2,lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NO: 14285-14296 or 14337-14339.

[0051] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 14297-14307 or 14340-14342. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 14297-14307 or 14340-14342, at least 80% identical to any one of SEQ ID NOs: 14297- 14307 or 14340-14342, at least 85% identical to of any one of SEQ ID NOs: 14297-14307 or 14340- 14342, at least 90% identical to any one of SEQ ID NOs: 14297-14307 or 14340-14342, or at least 95% identical to any one of SEQ ID NOs: 14297-14307 or 14340-14342. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 14297- 14307 or 14340-14342, 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: 14297-14307 or 14340-14342, 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: 14297-14307 or 14340-14342. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0052] Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 14285-14296 or 14337-14339. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 14297-14307 or 14340-14342. In any of SEQ ID NOs: 14285-14296 or 14337-14339, 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 beenmodified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 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: 14285-14296 or 14337-14339 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: 14285- 14296 or 14337-14339 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: 14285-14296 or 14337-14339 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: 14285-14296 or 14337-14339 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: 14285-14296 or 14337-14339 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337- 14339 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: 14285-14296 or 14337-14339 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337- 14339 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to aTor 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: 14285-14296 or 14337-14339 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337- 14339 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 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: 14285-14296 or 14337-14339 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to aC. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 14285-14296 or 14337-14339 is modified to a 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: 14285-14296 or 14337-14339 is modified to a C.

[0053] In some embodiments, any of the aforementioned siRNA comprising a sense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attachedto sense strand sequence of one of SEQ ID NOS: 1-6354, 13082-13402, 13951-14078, 14285-14296 or 14337-14339. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise a LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal- 6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28.Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine- glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 13951-14078, thymine (T) may be replaced with uracil (U).

[0054] In some embodiments, any of the aforementioned siRNA comprising an antisense stand comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand sequence of one of SEQ ID NO: 6355-12708, 13403-13723, 14079-14206, 14297- 14307 or 14340-14342. The antisense stand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise a LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal-6] s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial -specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 13951-14078, thymine (T) may be replaced with uracil (U).

[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 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 one 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 one of subset A. 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, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[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 B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one 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 one of subset B. 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 beenmodified to a U. Any of the aforementioned siRNAs may include an antisense strand of one of subsetB, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[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 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 one 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 one of subset C. 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 subsetC, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0058] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset 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 one of subset D. Any of the aforementionedsiRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of subset D. 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 D, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0059] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one 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 one of subset E. 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 E, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0060] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset 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, thesense 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 one 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 one of subset F. 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 F, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0061] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset 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. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one 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 one of subset I. 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 I, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementionedsequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset I). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset I.

[0062] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset 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 sense strand 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. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one 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 one of subset J. 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 J, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset J). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor(TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset J.

[0063] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset 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 one 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 one of subset K. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include an antisense strand of one of subset K, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0064] 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 L. 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 L. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset L, 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 L, 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 L. The sense strand or antisense strand may comprise any modifications described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of subset L. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one ofsubset L. 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 L, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset L). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset L.

[0065] 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 M. 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 M. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset M, 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 M, 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 M. The sense strand or antisense strand may comprise any modifications described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of subset M. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of subset M. 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 ofsubset M, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset M). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset M.

[0066] 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 N. 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 N. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset N, 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 N, 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 N. The sense strand or antisense strand may comprise any modifications described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of subset N. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of subset N. 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 N, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset N). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset N.

[0067] 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 O. 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 O. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset O, 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 O, 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 O. The sense strand or antisense strand may comprise any modifications described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of subset O. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of subset O. 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 O, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g., a different set of modifications or modification pattern than subset O). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2,lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense strand or antisense strand sequence of subset O.

[0068] In some embodiments, any of the aforementioned siRNA comprising a sense strand or antisense stand comprises a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to sense or anti sense strand sequence of one of Subset A, subset B, subset C, subset D, subset E, subset F, subset I, subset J, subset K, subset L, subset M, subset N or subset O. The sense strand or antisense stand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety, sense strand or antisense stand may comprise an integrin or an integrin targeting ligand. The sense strand or antisense stand may comprise an angiopep-2. The sense strand or antisense stand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The sense strand or antisense stand may comprise a LDL receptor ligand. Representative examples of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal-6] s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial -specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha- v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. In any of SEQ ID NOs: 13951-14078, thymine (T) may be replaced with uracil (U).

[0069] 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 herein (such as an siRNA in a table herein). 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 an siRNA herein. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of an siRNA herein, 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 an siRNA herein, 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 an siRNA herein. The sense strand or antisense strand may comprise an overhang. 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. In some embodiments, the siRNA comprises a sensestrand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101. 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 Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101, 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 Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101, 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 Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101. The sense strand or antisense strand may comprise an overhang. 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 or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 2856-3037.Representative example of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 , L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus or THA. Preferably, the GalNAc moiety is ETL17. Representative example of lipid moiety includes, but is not limited to, ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL22, or ETL28. Preferably, the lipid moiety is ETL20. Representative example of integrin or integrin targeting ligand includes, but is not limited to, epithelial -specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0070] Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101. 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. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisensestrand comprise a oligonucleotide sequences as disclosed in Table 8, 13, 17, 21, 24, 30, 34, 48, 62,67. 68, 75, 79, 83, 86, 91, 96, or 101, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Table 8, 13, 17, 21, 24, 30, 34, 48, 62, 67, 68, 75, 79, 83, 86, 91, 96, or 101

[0071] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 8, 13, 17, 21, 24, 27,30. 34. 48. 62. 64. 65. 67. 68, 75, 79, 83, 86, 91, 96 and 101, each strand is independently about 19- 21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Table 8, 13, 17, 21, 24, 27, 30, 34, 48, 62, 64, 65, 67, 68, 75, 79, 83, 86, 91, 96 and 101

[0072] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ IDNOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166, 13167, 13168, 13169, 13170,13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160, 13161, 13162, 13163, 13164, 13344,13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222, 13223, 13224, 13307, 13308, 13309,13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270, 13271, 13272, 13273, 13998, 13974,13980, and 13274. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165,13166, 13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160,13161, 13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222,13223, 13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270,13271, 13272, 13273, 13998, 13974, 13980, and 13274., at least 80% identical to any one of SEQ ID NOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166, 13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160, 13161, 13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222, 13223, 13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270, 13271, 13272, 13273, 13998, 13974, 13980, and 13274., at least 85% identical to of any one of SEQ ID NOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166,13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160, 13161,13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222, 13223,13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270, 13271,13272, 13273, 13998, 13974, 13980, and 13274., at least 90% identical to any one of SEQ IDNOsl3329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166, 13167, 13168, 13169, 13170, 13171, 13172, 13173,13100, 13157, 13158, 13159, 13160, 13161, 13162, 13163, 13164, 13344, 13103, 13216, 13217,13218, 13219, 13220, 13221, 13222, 13223, 13224, 13307, 13308, 13309, 13310, 13345, 13346,13106, 13267, 13268, 13269, 13270, 13271, 13272, 13273, 13998, 13974, 13980, and 13274., or at least 95% identical to any one of SEQ ID NOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166, 13167,13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160, 13161, 13162,13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222, 13223, 13224,13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270, 13271, 13272,13273, 13998, 13974, 13980, and 13274. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099, 13165, 13166,13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159, 13160, 13161,13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221, 13222, 13223,13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269, 13270, 13271,13272, 13273, 13998, 13974, 13980, and 13274., 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: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341, 13099,13165, 13166, 13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158, 13159,13160, 13161, 13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220, 13221,13222, 13223, 13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268, 13269,13270, 13271, 13272, 13273, 13998, 13974, 13980, and 13274., 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: 13329, 13334, 13335, 13091, 13259, 13260, 13261, 13262, 13263, 13264, 13265, 13266, 13336, 13311, 13312, 13341,13099, 13165, 13166, 13167, 13168, 13169, 13170, 13171, 13172, 13173, 13100, 13157, 13158,13159, 13160, 13161, 13162, 13163, 13164, 13344, 13103, 13216, 13217, 13218, 13219, 13220,13221, 13222, 13223, 13224, 13307, 13308, 13309, 13310, 13345, 13346, 13106, 13267, 13268,13269, 13270, 13271, 13272, 13273, 13998, 13974, 13980, and 13274. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. Any of the aforementioned siRNAs may include asense strand that lacks a 3’ A of a sense strand sequence. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662,13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492, 13493, 13494, 13421, 13478, 13479,13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424, 13537, 13538, 13539, 13540, 13541,13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631, 13666, 13667, 13427, 13588, 13589,13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or 13595. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662, 13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492, 13493,13494, 13421, 13478, 13479, 13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424, 13537,13538, 13539, 13540, 13541, 13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631, 13666,13667, 13427, 13588, 13589, 13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or 13595, at least 80% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662, 13420, 13486, 13487, 13488,13489, 13490, 13491, 13492, 13493, 13494, 13421, 13478, 13479, 13480, 13481, 13482, 13483,13484, 13485, 13665, 13424, 13537, 13538, 13539, 13540, 13541, 13542, 13543, 13544, 13545,13628, 13629, 13630, 13631, 13666, 13667, 13427, 13588, 13589, 13590, 13591, 13592, 13593,13594, 14126, 14102, 14108, or 13595, at least 85% identical to of any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632,13633, 13662, 13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492, 13493, 13494, 13421,13478, 13479, 13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424, 13537, 13538, 13539,13540, 13541, 13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631, 13666, 13667, 13427,13588, 13589, 13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or 13595, at least 90% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662, 13420, 13486, 13487, 13488, 13489,13490, 13491, 13492, 13493, 13494, 13421, 13478, 13479, 13480, 13481, 13482, 13483, 13484,13485, 13665, 13424, 13537, 13538, 13539, 13540, 13541, 13542, 13543, 13544, 13545, 13628,13629, 13630, 13631, 13666, 13667, 13427, 13588, 13589, 13590, 13591, 13592, 13593, 13594,14126, 14102, 14108, or 13595, or at least 95% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633,13662, 13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492, 13493, 13494, 13421, 13478,13479, 13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424, 13537, 13538, 13539, 13540,13541, 13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631, 13666, 13667, 13427, 13588,13589, 13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or 13595. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657,13632, 13633, 13662, 13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492, 13493, 13494,13421, 13478, 13479, 13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424, 13537, 13538,13539, 13540, 13541, 13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631, 13666, 13667,13427, 13588, 13589, 13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or 13595, 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: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662, 13420, 13486, 13487, 13488, 13489, 13490, 13491, 13492,13493, 13494, 13421, 13478, 13479, 13480, 13481, 13482, 13483, 13484, 13485, 13665, 13424,13537, 13538, 13539, 13540, 13541, 13542, 13543, 13544, 13545, 13628, 13629, 13630, 13631,13666, 13667, 13427, 13588, 13589, 13590, 13591, 13592, 13593, 13594, 14126, 14102, 14108, or13595, 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: 13650, 13655, 13656, 13412, 13580, 13581, 13582, 13583, 13584, 13585, 13586, 13587, 13657, 13632, 13633, 13662, 13420, 13486, 13487, 13488, 13489, 13490,13491, 13492, 13493, 13494, 13421, 13478, 13479, 13480, 13481, 13482, 13483, 13484, 13485,13665, 13424, 13537, 13538, 13539, 13540, 13541, 13542, 13543, 13544, 13545, 13628, 13629,13630, 13631, 13666, 13667, 13427, 13588, 13589, 13590, 13591, 13592, 13593, 13594, 14126,14102, 14108, or 13595. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence.

[0073] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276, 13280, 13360,13317, 13365, 13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284, 13377, 13382,13383, 13292, 13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258, 13393, 13394,13299, 14126, 14102, 14108, or 13300. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13329, 13334, 13335,13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267,13268, 13353, 13358, 13359, 13276, 13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368,13241, 13369, 13370, 13283, 13284, 13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389,13202, 13207, 13195, 13392, 13258, 13393, 13394, 13299, 14126, 14102, 14108, or 13300, at least80% identical to any one of SEQ ID NOs: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276,13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284,13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258,13393, 13394, 13299, 14126, 14102, 14108, or 13300, at least 85% identical to of any one of SEQ IDNOs: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276, 13280, 13360, 13317, 13365,13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284, 13377, 13382, 13383, 13292,13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258, 13393, 13394, 13299, 14126,14102, 14108, or 13300, at least 90% identical to any one of SEQ ID NOs 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267,13268, 13353, 13358, 13359, 13276, 13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368,13241, 13369, 13370, 13283, 13284, 13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389,13202, 13207, 13195, 13392, 13258, 13393, 13394, 13299, 14126, 14102, 14108, or 13300, or at least 95% identical to any one of SEQ ID NOs: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276,13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284,13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258,13393, 13394, 13299, 14126, 14102, 14108, or 13300. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13329, 13334, 13335,13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267,13268, 13353, 13358, 13359, 13276, 13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368,13241, 13369, 13370, 13283, 13284, 13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389,13202, 13207, 13195, 13392, 13258, 13393, 13394, 13299, 14126, 14102, 14108, or 13300, 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: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276, 13280, 13360, 13317, 13365,13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284, 13377, 13382, 13383, 13292,13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258, 13393, 13394, 13299, 14126,14102, 14108, or 13300, 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: 13329, 13334, 13335, 13260, 13264, 13336, 13311, 13341, 13168, 13173, 13161, 13344, 13224, 13345, 13346, 13267, 13268, 13353, 13358, 13359, 13276,13280, 13360, 13317, 13365, 13185, 13190, 13178, 13368, 13241, 13369, 13370, 13283, 13284,13377, 13382, 13383, 13292, 13296, 13384, 13323, 13389, 13202, 13207, 13195, 13392, 13258,13393, 13394, 13299, 14126, 14102, 14108, or 13300. The sense strand sequence may include thefirst 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand.

[0074] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588, 13589, 13674, 13679, 13680, 13597,13601, 13681, 13638, 13686, 13506, 13511, 13499, 13689, 13562, 13690, 13691, 13604, 13605,13698, 13703, 13704, 13613, 13617, 13705, 13644, 13710, 13523, 13528, 13516, 13713, 13579,13714, 13715, 13620, 14126, 14102, 14108, or 13621. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 13650,13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666,13667, 13588, 13589, 13674, 13679, 13680, 13597, 13601, 13681, 13638, 13686, 13506, 13511,13499, 13689, 13562, 13690, 13691, 13604, 13605, 13698, 13703, 13704, 13613, 13617, 13705,13644, 13710, 13523, 13528, 13516, 13713, 13579, 13714, 13715, 13620, 14126, 14102, 14108, or 13621, at least 80% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588, 13589, 13674, 13679,13680, 13597, 13601, 13681, 13638, 13686, 13506, 13511, 13499, 13689, 13562, 13690, 13691,13604, 13605, 13698, 13703, 13704, 13613, 13617, 13705, 13644, 13710, 13523, 13528, 13516,13713, 13579, 13714, 13715, 13620, 14126, 14102, 14108, or 13621, at least 85% identical to of any one of SEQ ID NOs: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588, 13589, 13674, 13679, 13680, 13597, 13601, 13681,13638, 13686, 13506, 13511, 13499, 13689, 13562, 13690, 13691, 13604, 13605, 13698, 13703,13704, 13613, 13617, 13705, 13644, 13710, 13523, 13528, 13516, 13713, 13579, 13714, 13715,13620, 14126, 14102, 14108, or 13621, at least 90% identical to any one of SEQ ID NOs: 13650,13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666,13667, 13588, 13589, 13674, 13679, 13680, 13597, 13601, 13681, 13638, 13686, 13506, 13511,13499, 13689, 13562, 13690, 13691, 13604, 13605, 13698, 13703, 13704, 13613, 13617, 13705,13644, 13710, 13523, 13528, 13516, 13713, 13579, 13714, 13715, 13620, 14126, 14102, 14108, or 13621, or at least 95% identical to any one of SEQ ID NOs: 13650, 13655, 13656, 13581, 13585,13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588, 13589, 13674,13679, 13680, 13597, 13601, 13681, 13638, 13686, 13506, 13511, 13499, 13689, 13562, 13690,13691, 13604, 13605, 13698, 13703, 13704, 13613, 13617, 13705, 13644, 13710, 13523, 13528,13516, 13713, 13579, 13714, 13715, 13620, 14126, 14102, 14108, or 13621. In some embodiments,the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545,13666, 13667, 13588, 13589, 13674, 13679, 13680, 13597, 13601, 13681, 13638, 13686, 13506,13511, 13499, 13689, 13562, 13690, 13691, 13604, 13605, 13698, 13703, 13704, 13613, 13617,13705, 13644, 13710, 13523, 13528, 13516, 13713, 13579, 13714, 13715, 13620, 14126, 14102,14108, or 13621, 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: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588, 13589, 13674, 13679, 13680, 13597,13601, 13681, 13638, 13686, 13506, 13511, 13499, 13689, 13562, 13690, 13691, 13604, 13605,13698, 13703, 13704, 13613, 13617, 13705, 13644, 13710, 13523, 13528, 13516, 13713, 13579,13714, 13715, 13620, 14126, 14102, 14108, or 13621, or an antisense strand sequence thereof having1 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: 13650, 13655, 13656, 13581, 13585, 13657, 13632, 13662, 13489, 13494, 13482, 13665, 13545, 13666, 13667, 13588,13589, 13674, 13679, 13680, 13597, 13601, 13681, 13638, 13686, 13506, 13511, 13499, 13689,13562, 13690, 13691, 13604, 13605, 13698, 13703, 13704, 13613, 13617, 13705, 13644, 13710,13523, 13528, 13516, 13713, 13579, 13714, 13715, 13620, 14126, 14102, 14108, or 13621. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence.

[0075] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 13998. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 13998, at least 80% identical to any one of SEQ ID NO: 13998, at least 85% identical to of any one of SEQ ID NO: 13998, at least 90% identical to any one of SEQ ID No: 13998, or at least 95% identical to any one of SEQ ID NO: 13998. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 13998, 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 NO: 13998, 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 NO: 13998. 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 the5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 13998. The sense strand may comprise an overhang. 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. The sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand.

[0076] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NO: 14126. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 14126, at least 80% identical to any one of SEQ ID NO: 14126, at least 85% identical to of any one of SEQ ID NO: 14126, at least 90% identical to any one of SEQ ID NO: 14126, or at least 95% identical to any one of SEQ ID NO: 14126. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 14126, 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 NO: 14126, 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 NO: 14126. 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 ofnucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand.

[0077] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 13974. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 13974, at least 80% identical to any one of SEQ ID NO: 13974, at least 85% identical to of any one of SEQ ID NO: 13974, at least 90% identical to any one of SEQ ID No: 13998, or at least 95% identical to any one of SEQ ID NO: 13974. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 13974, 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 NO: 13974, 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 NO: 13974. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 13974. The sense strand may comprise an overhang. 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. The sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand.

[0078] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NO: 14102. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 14102, at least 80% identical to any one of SEQ ID NO: 14102, at least 85% identical to of any one of SEQ ID NO: 14102, at least 90% identical to any one of SEQ ID NO: 14102, or at least 95% identical to any one of SEQ ID NO: 14102. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 14102, 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 NO: 14102, 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 NO: 14102. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, andLDL receptor ligand. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand.

[0079] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 13980. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 13980, at least 80% identical to any one of SEQ ID NO: 13980, at least 85% identical to of any one of SEQ ID NO: 13980, at least 90% identical to any one of SEQ ID No: 13980, or at least 95% identical to any one of SEQ ID NO: 13980. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 13980, 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 NO: 13980, 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 NO: 13980. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 13980. The sense strand may comprise an overhang. 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. The sense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. The sense strand may comprise an angiopep-2. The sense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The sense strand may comprise a glucose transporter protein. The sense strand may comprise an LDL receptor ligand.

[0080] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NO: 14108. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NO: 14108, at least 80% identical to any one of SEQ ID NO: 14108, at least 85% identical to of any one of SEQ ID NO: 14126, at least 90% identical to any one of SEQ ID NO: 14108, or at least 95% identical to any one of SEQ ID NO: 14108. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NO: 14108, 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 NO: 14108, 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 NO: 14108. 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. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. The antisense strand may comprise a lipid moiety or a GalNAc moiety. The antisense strand may comprise an integrin or an integrin targeting ligand. The antisense strand may comprise an angiopep-2. The antisense strand may comprise a lipoprotein receptor related protein (LRP) ligand. The antisense strand may comprise a glucose transporter protein. The antisense strand may comprise an LDL receptor ligand.B. ASOs

[0081] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17,18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0082] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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 GPAM mRNA sequence such as SEQ ID NO: 12867; 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: 12867.C. Modification patterns

[0083] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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 intemucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate tri ester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or AS Os. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0084] 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.

[0085] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises a modified intemucleoside 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 intemucleoside 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 intemucleoside linkages, 4 or more modified intemucleoside 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.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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'-O-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 HLA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O- methoxy ethyl group (“MOE”). In some embodiments, the modified nucleoside comprises a 2'-C-alkyl group. In some embodiments, the modified nucleoside comprises 2’ -methoxyethyl. For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’ -O-methoxyethyl thymine. In some embodiments, the modified nucleoside comprises 2'-O-methyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'- deoxy fluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In someembodiments, 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 acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0087] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:

[0088] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:wherein the base can be any pyrimidine or purine.

[0089] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:where J and K are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodi ester or phosphorothioate bond.

[0090] 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:(5’ methylphosphonate 2’-O-methyl Uridine).

[0091] 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.

[0092] 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.

[0093] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0094] 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.

[0095] 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 a2’-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.

[0096] 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.

[0097] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’ -O-methyl and 2’ -O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ -O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’ -O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’- fluoro and 2’ -O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methoxy ethyl, 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.

[0098] 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 atposition 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.

[0099] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro; all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O- methyl; all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; or all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides comprise 2’ -fluoro. In some embodiments, all purine nucleosides comprise 2’ - fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O- methyl; all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides comprise 2’ -fluoro.

[0100] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0102] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety mayinclude an N- acetyl galactose moiety (e.g., anN-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.

[0103] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0104] 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.

[0105] In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’ - fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’ -methyl modification may be included, and vice versa.

[0106] 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.

[0107] 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.

[0108] 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-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines.

[0109] In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methylmodified 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.

[0110] 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.

[0111] 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.

[0112] 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 modifiedpyrimi dines, and all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines.

[0113] 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.

[0114] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between 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’Fmodifi cations 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.

[0115] 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.

[0116] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group includes a cell receptor ligand, such as an integrin targeting ligand. Integrins may include a family of transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. In some embodiments, the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 (αvβ6) bay be an example of an epithelial-specific integrin αvβ6 may be a receptor for an ECM protein or TGF-beta latency- associated peptide (LAP). Integrin αvβ6 may be expressed in a cell or tissue. Integrin αvβ6 may be expressed or upregulated in injured pulmonary epithelium.

[0117] In some embodiments, the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin αvβ6. An integrin targeting ligand may include a compound that has affinity for integrin αvβ6 or integrin alpha- v-beta-3 (αvβ3), may be useful as a ligand to facilitate targeting or delivery of the oligonucleotide to which it is attached to a particular cell type or tissue (e.g., to cells expressing integrin αvβ3 or αvβ6). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the oligonucleotide-integrin targeting ligand conjugates are selectively internalized by chondrocytes, either through receptor-mediated endocytosis or by other means.

[0118] In some embodiments, an oligonucleotide that targets GPAM 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).

[0119] 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 GPAM, 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 isattached 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.

[0120] 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 deoxyribonucleotides.

[0121] 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 someembodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine; all pyrimidine of the sense strand comprises 2’- O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’- fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd- numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’-fluoro-modified pyrimidines in a row.

[0122] 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.

[0123] 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 modifiednucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxy ribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0124] 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.

[0125] 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.

[0126] 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

[0127] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide intissues. 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.

[0128] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.1. Hydrophobic moieties

[0129] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0130] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0131] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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 is 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.

[0132] In some embodiments, ahydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[0133] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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 hydrophobic moiety may include an esterified lipid.

[0134] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure:In some embodiments, the oligonucleotide comprisesany 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.

[0135] 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

[0136] 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 16carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.

[0137] 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.

[0138] 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:In some 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 someembodiments, 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, 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 the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.

[0139] The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose). A phosphate ofthe 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.

[0140] 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.

[0141] 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 phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:orIn 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, 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, or20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the 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.

[0142] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0143] 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

[0144] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N- acetyl galactose moiety (e.g., anN-acetylgalactosamine (GalNAc) moiety), an N-acetylglucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N- acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0145] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, 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.

[0146] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0147] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of GPAM, 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:C3-10carbocycle 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 C1-6alkyl, wherein the C1-6alkyl, 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:C1-6alkyl 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; andC1-6alkyl 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;C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C3-10carbocycle, and 3- to 10-membered heterocycle; andC3-10carbocycle, 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- C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, and C 1 -6 haloalky 1.(2) In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, - OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH,-SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, 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(OR^O-, -OP(N(R7)2)O-, - OP(OR7)N(R7)-, and -OPN(R7)2NR7. 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-, 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 -OP(OR7)O-. 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 Ci -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 C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkylX, -NH(C1-6alkyl), C3-10carbocycle, or 3- to 10- membered heterocycle. In some embodiments, each R7is independently selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, and -NH(C1-6alkyl). In some embodiments, each R7is independently selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O-) O-, -OP(S)(Q- )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 some embodiments, the compound comprises:

[0148] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphor odi thioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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 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.

[0157] Some embodiments include the following, where the phosphate or “5 ’ ” indicates a connectiono the oligonucleotide:

[0158] Some embodiments include the following, where the phosphate or “5 ’ ” indicates a connection to the oligonucleotide:

[0159] 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.

[0160] 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.

[0161] Some embodiments include the following, where J is the oligonucleotide:. J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.Some embodiments include the following, where J is the oligonucleotide:. 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.

[0162] 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.

[0163] 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 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 Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein theoligonucleotide 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):or a saltthereof, 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: C3-20cyclic, 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 C1-6alkyl, wherein the C1-6alkyl, 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, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C3-10carbocycle, and 3- to 10-membered heterocycle, C3-10carbocycle, 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-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, and C1-6haloalkyl.

[0164] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0165] 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 phosphor othi oates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0166] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0167] 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 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 phosphorothi oates linking to the oligonucleotide. J in some instances comprises a phosphorothi oate linking to the oligonucleotide.

[0168] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0169] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0170] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0171] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or 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 phosphorothi oates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0172] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[0173] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moi eties. R in some instances comprises one or more phosphates or phosphorothi oates 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.

[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) 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.

[0175] 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 theoligonucleotide. 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:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more 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.

[0177] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0178] 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.

[0179] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0180] 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 phosphor othi oates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0181] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0182] 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 ormore phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking to the oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0183] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0159] 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 phosphorothioate linking to the oligonucleotide.

[0160] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:

[0184] 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.

[0185] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0186] 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 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.

[0187] Provided herein are sugar moieties comprising the following structure, where J and J’ is an oligonucleotide or a GalNAc moiety:

[0188] 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 phosphorothi oates 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 phosphorothi oates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0189] 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:

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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 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.

[0194] 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 “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. Modified siRNAs

[0195] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification

[0196] In all the above modification pattern, wherever they occur, “Nf” is a 2’ -fluoro-modified nucleoside, “n” is a 2’ -O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’-deoxy-modified nucleoside or a 2’ -deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’ -O-methyl inosine nucleoside, N(C16) is 2’-O- hexadecate modification andN comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.modification pattern, wherever they occur, “Nf” is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’ -deoxymodified nucleoside or a 2’ -deoxy nucleoside, “nm” is a 2’ -O-methoxy ethyl modified nucleoside, “i” is an inosine, “ni” is a2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification, VP is a 5'- vinyl phosphonate, “[NUNA]” is an unlocked nucleic acid, “[UNA]” is an unlocked nucleic acid and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0198] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of GPAM, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50As, 51AS, 52AS, 53AS, 54AS 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61 AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 5OAs, 51AS, 52AS, 53AS, 54AS 55AS, 56AS, 57AS, 58AS, 59AS, 60 AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, 69AS, 70AS, 71 AS, or72AS . In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS,33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS,47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS,61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS,63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20 AS, 21AS, 22 AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS,26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS,40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS,54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67 AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS,31AS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS,45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS,59AS, 60AS, 61 AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS,47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS,61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15 AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS,9 AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20 AS, 21AS, 22 AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS,26AS, 27 AS, 28AS, 29 AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS,40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS,54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67 AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15 AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61 AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15 AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15 AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS,35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20 AS, 21AS, 22 AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS,26AS, 27 AS, 28AS, 29 AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS,40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS,54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67 AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61 AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 23 S and the antisense strand comprises pattern 1AS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS,61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67 AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20 AS, 21AS, 22 AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS,26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS,40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS,54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67 AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13 AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 A...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount decreases circulating cholesterol, apolipoprotein B, bilirubin, alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase in a subject, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69AS.

2. The composition of claim 1, wherein the cholesterol comprises total cholesterol, low density lipoprotein cholesterol, or non-high density lipoprotein cholesterol.

3. The composition of claim 1, wherein the cholesterol is decreased by about 10% or more, as compared to prior to administration.

4. A composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount decreases a liver fibrosis score, non-alcoholic fatty liver disease (NAFLD) activity score, or liver fat percentage in a subject, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69AS.

5. The composition of claim 4, wherein the decrease is by about 10% or more, as compared to prior to administration.

6. A composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount decreases a use of statin (HMG CoA reductase inhibitor) medication, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69AS.

7. The composition of claim 6, wherein the decrease is by about 10% or more, as compared to prior to administration.

8. A composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount improves a measurement that reflects a phenotype of esophageal varices, portal hypertension, NAFLD, NASH, alcoholic liver disease, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, hyperlipidemia, ischemic heart disease, or coronary heart disease in a subject, wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 60S, 61S, 55S, 56AS, 9AS, 57AS, 30AS, 58AS, 68AS, and 69AS.

9. The composition of claim 8, wherein the improvement is by about 10% or more, as compared to prior to administration.

10. A composition comprising an siRNA that targets GPAM and when administered to a subject in an effective amount increases circulating ketone bodies in a subject wherein the siRNA comprises a modification pattern selected from the group consisting of 54S, 53S, 57S, 56S, 109S, 114S, 52S, 157S, 158S, 159S, 160S, 161S, 162S, 163S, 164S, 68AS, 69AS, 70AS, 71AS, and 72AS.

11. The composition of claim 10, wherein the increase is by about 10% or more, as compared to prior to administration.

12. The composition of any one of claims 1-11, wherein the oligonucleotide comprises an N- acetylgalactosamine (GalNAc) moiety, anN-acetylglucosamine (GlcNAc) moiety, or a mannose moiety, attached at a 3’ or 5’ terminus of the oligonucleotide.

13. The composition of any one of claims 1-12, wherein the oligonucleotide comprises a GalNAc moiety.

14. The composition of claim 13, comprising:, wherein J comprises the oligonucleotide, and wherein J comprises an optional phosphate or phosphorothioate linking to the oligonucleotide.

15. The composition of any one of claims 1-14, wherein the siRNA comprises a sense strand and an antisense strand.

16. The composition of claim 15, wherein the sense strand comprises a sequence comprising at least 19 nucleosides of any one of SEQ ID NO: 1-6354, 13082-13402, 13951-14078, or 14285-14296, or 14337-14339.

17. The method of claim 15 or 16 wherein the antisense strand comprises a sequence comprising at least 19 nucleosides of any one of SEQ ID NO: 6355-12708, 13403-13723, 14079-14206, 14297- 14307, or 14340-14342.

18. A composition comprising an oligonucleotide that inhibits the expression of GP AM, 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 siRNA comprises sense sequence comprising any one of SEQ ID NO: 13780-13840, 13914-13937, 14254-14255, 14308-14319, or 14331- 14333or an antisense sequence comprising any one of SEQ ID NO: 13841-13913, 13938-13950, 14207- 14253, 14256-14276, 14277-14284, 14320-14330, or 14334-14336.

19. The composition of any one of claims 1-18, further comprising a pharmaceutically acceptable carrier.

20. A method of treating a subject having liver disease, comprising administering an effective amount of the composition of claim 19 to the subject.

21. The method of claim 20, wherein the liver disease comprises NAFLD, NASH, alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma.

22. A method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition of claim 19 to the subject.

23. The method of claim 22, wherein the cardiometabolic disease comprises hyperlipidemia, ischemic heart disease, or coronary heart disease.

24. A method of treating a subject having liver disease, the method comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist.

25. The method of claim 24, wherein the liver disease comprises NAFLD (or MASLD), NASH (or MASH), alcoholic liver disease, liver fibrosis, liver cirrhosis, or hepatocellular carcinoma.

26. The method of claim 24, wherein the GLP-1 receptor agonist comprises exenatide, lixisenatide, liraglutide, dulaglutide, tirzepatide, dulaglutide, semaglutide or a combination thereof.

27. A method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist.

28. The method of claim 27, wherein the cardiometabolic disease comprises hyperlipidemia, ischemic heart disease, or coronary heart disease.

29. The method of claim 27, wherein the GLP-1 receptor agonist comprises exenatide, lixisenatide, liraglutide, dulaglutide, tirzepatide, dulaglutide, semaglutide or a combination thereof.

30. A composition comprising an oligonucleotide that inhibits the expression of GP AM in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, 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 siRNA comprises sense sequence comprising any one of SEQ ID NO: 13780-13840, 13914-13937, 14254-14255, 14308-14319, or 14331- 14333or an antisense sequence comprising any one of SEQ ID NO: 13841-13913, 13938-13950, 14207- 14253, 14256-14276, 14277-14284, 14320-14330, or 14334-14336.

31. A method of treating a subject having liver disease, the method comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, GIP receptor antagonist, glucagon receptor agonist, amylin receptor agonist, apelin receptor agonist, peptide YY receptor agonist, calcitonin receptor agonist, growth differentiation factor-15 (GDF15) analogue, fibroblast growth factor 21 (FGF21) analog, fibroblast growth factor 21 (FGF19) analog, peroxisome proliferator -activated receptors (PPAR) agonist, thyroid hormone receptor-β agonist, FXR agonist, antagonist or modulator of inhibin βE (INHBE) / activin E expression or function, antagonist or modulator of activin receptor-like kinase 7 (ALK7) expression or function, antagonist or modulator of diacylglycerol acyltransferase (DGAT) or acetyl-CoA carboxylase (ACC) expression or function, antagonist or modulator of patatin-like phospholipase domain- containing protein 3 (PNPLA3) expression or function, antagonist or modulator of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13)expression or function, antagonist or modulator of mitochondrial amidoxime-reducing component 1 (MTARC1) expression or function, or a combination thereof.

32. A method of treating a subject having cardiometabolic disease, comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one GLP-1 receptor agonist, glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, GIP receptor antagonist, glucagon receptor agonist, amylin receptor agonist, apelin receptor agonist, peptide YY receptor agonist, calcitonin receptor agonist, growth differentiation factor-15 (GDF15) analogue, fibroblast growth factor 21 (FGF21) analog, fibroblast growth factor 21 (FGF19) analog, peroxisome proliferator -activated receptors (PPAR) agonist, thyroid hormone receptor-β agonist, FXR agonist, antagonist or modulator of inhibin βE (INHBE) / activin E expression or function, antagonist or modulator of activin receptor-like kinase 7 (ALK7) expression or function, antagonist or modulator of diacylglycerol acyltransferase (DGAT) or acetyl-CoA carboxylase (ACC) expression or function, antagonist or modulator of patatin-like phospholipase domain- containing protein 3 (PNPLA3) expression or function, antagonist or modulator of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) expression or function, antagonist or modulator of mitochondrial amidoxime-reducing component 1 (MTARC1) expression or function, or a combination thereof.

33. A method of treating a subject having liver or cardiometabolic disease, comprising administering an effective amount of the composition of claim 19 to the subject in combination with therapeutically effective amount of at least one additional active agent.