Inhibin subunit beta e-related double stranded oligonucleotide compositions and methods relating thereto

Abstract

The present disclosure provides inhibin subunit beta E (INHBE)-related double stranded oligonucleotides, compositions, and methods of using the same, either alone or in combination with additional therapeutics, for preventing and / or treating various INHBE- related disorders, including maintenance of weight loss achieved with such double stranded oligonucleotides, compositions comprising the same, and / or other therapeutics. In some embodiments, the provided double stranded oligonucleotides and compositions comprise nucleobase modifications, sugar modifications, internucleotidic linkage modifications and / or patterns thereof, and have improved properties, activities and / or selectivities. In some embodiments, the provided double stranded oligonucleotides and compositions target INHBE.

Description

[0001]088290.0189 INHIBIN SUBUNIT BETA E-RELATED DOUBLE STRANDED OLIGONUCLEOTIDE COMPOSITIONS AND METHODS RELATING THERETO RELATED APPLICATIONS 5 This application claims the benefit of priority to United States Provisional Application Serial Nos.63 / 645,058, filed May 9, 2024; 63 / 680,974, filed August 8, 2024; 63 / 713,973, filed October 30, 2024; and 63 / 768,140, filed March 6, 2025, the contents of all of which are incorporated by reference herein in their entireties. TECHNICAL FIELD 10 Among other things, the present disclosure provides double stranded (ds) oligonucleotides, compositions and methods (e.g., of preparation, use, etc.) thereof. In some embodiments, provided technologies are useful for preventing and / or treating various conditions, disorders, or diseases associated with inhibin subunit beta E (INHBE) expression. BACKGROUND 15 Metabolic disorders, e.g., metabolic syndrome, and related diseases, e.g., obesity, cardiovascular disease, diabetes, and hypertension are an increasing medical concern. Typical treatment for such disorders and diseases involves targeted approaches and / or changes in diet and lifestyle, e.g., increased physical activity. Particularly, treatment for obesity, which is a disorder involving excess body fat, entails exercise and a healthy, balanced diet leading to 20 weight loss. There exists, however, a need for alternate treatment methods for metabolic diseases, particularly weight loss. Double stranded (ds) oligonucleotides are useful in various applications, e.g., therapeutic, diagnostic, and / or research applications. Inhibin subunit beta E (INHBE), which is primarily expressed in the liver, has been linked with both body mass index and insulin 25 resistance. As such, ds oligonucleotides targeting disorders or diseases associated with expression of INHBE can be useful treatment of such conditions including metabolic disorders, e.g., metabolic syndrome, and related diseases, e.g., obesity, cardiovascular disease, diabetes, and hypertension. SUMMARY 30 In some embodiments, the present disclosure provides ds oligonucleotides targeting INHBE and compositions thereof that have significantly improved properties and / or high activities. Among other things, the present disclosure provides technologies for designing, 1 088290.0189 manufacturing and utilizing such ds oligonucleotides and compositions. Particularly, in some embodiments, the present disclosure provides ds oligonucleotides comprising useful patterns of internucleotidic linkages and / or patterns of sugar modifications, which, when combined with one or more other structural elements, e.g., base sequence (or portion thereof), nucleobase 5 modifications (and patterns thereof), additional chemical moieties, etc., can provide ds oligonucleotides targeting INHBE and compositions thereof with high activities and / or desired properties, including but not limited to effective and efficient reduction of expression, levels and / or activities of INHBE transcripts and products encoded thereby. In some embodiments, ds oligonucleotides targeting INHBE and compositions reduce levels of a INHBE transcript, 10 and are useful for treating and / or preventing INHBE-associated condition, disorder, or disease, including, but not limited to metabolic disorders, e.g., metabolic syndrome, and related diseases, e.g., obesity, cardiovascular disease, diabetes, and hypertension. In some embodiments, a ds oligonucleotide targeting INHBE is capable of mediating knockdown of INHBE, wherein the level, expression and / or activity of INHBE or a product 15 thereof are decreased. In some embodiments, a ds oligonucleotide targeting INHBE is capable of mediating pan-specific knockdown of INHBE, wherein the level, expression and / or activity of multiple or all INHBE alleles are decreased. In some embodiments, a ds oligonucleotide targeting INHBE has a base sequence that is complementary to a sequence which is common in multiple or all INHBE alleles. 20 In certain embodiments, such structural elements include one or more of: (1) chemical modifications (e.g., modifications of a sugar, base and / or internucleotidic linkage) and patterns thereof; and (2) alterations in stereochemistry (e.g., stereochemistry of a backbone chiral internucleotidic linkage) and patterns thereof. One or more of such structural elements can, in certain embodiments, be independently present in one or both oligonucleotides of a ds 25 oligonucleotide. In certain embodiments, the properties and / or activities impacted by such structural elements include, but are not limited to, participation in, direction of a decrease in expression, activity or level of a gene or a gene product thereof, mediated, for example, by RNA interference (RNAi interference). In certain embodiments, the present disclosure demonstrates that compositions 30 comprising ds oligonucleotides (e.g., dsRNAi oligonucleotides, also referred to as dsRNAi agents) with controlled structural elements provide unexpected properties and / or activities. In certain embodiments, the present disclosure encompasses the recognition that stereochemistry, e.g., stereochemistry of backbone chiral centers, can unexpectedly maintain or improve properties of ds oligonucleotides. 2 088290.0189 In a first aspect, the instant disclosure relates to a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 5 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 10 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 15 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and 20 the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or 25 an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 3 088290.0189 In certain embodiments of the first aspect, the guide strand comprises a 5’ terminal , 5 , , , and 4 088290.0189 e the base is selected from A, C, G, T, U, abasic, and modified nucleobases, R1is selected from H, OH, O-alkyl, O-methyl (O-Me), F, O-methoxyethyl (MOE), and 2’-O,4’C-methylene-bridged or locked nucleic acid (2’,4’-BNA or LNA), and R2is selected from alkyl, methyl, ethyl, isopropyl, propyl, cyclohexyl, benzyl, phenyl, tolyl, 5 xylyl, aryl, and arene group. In exemplary embodiments of the invention, the guide strand further comprises a 5’ terminal modification selected from, e.g., the group consisting of, e.g.: 10 5 088290.0189 5 6 088290.0189 5 10 7 088290.0189 5 8 088290.0189 5 9 088290.0189 10 10 088290.0189 11 088290.0189 12 088290.0189 5 13 088290.0189 5 10 14 088290.0189 , wherein the base is A, C, G, T, U, abasic, or a modified nucleobase; R1is selected from H, OH, O-alkyl, O-methyl (O-Me), F, O-methoxyethyl (MOE), and 2’-O,4’C-methylene-bridged or locked nucleic acid (2’,4’-BNA or LNA); R2is selected from alkyl, methyl, ethyl, isopropyl, propyl, cyclohexyl, benzyl, phenyl, tolyl, xylyl, aryl, and 5 arene group; and R6is selected from H, methyl, ethyl, isopropyl, propyl, cyclohexyl, benzyl, phenyl, tolyl, xylyl, aryl, and arene group. In an exemplary embodiment, the 5’ terminal modification is triazolyl phosphonate or methyl phosphonate. In an exemplary embodiment, the 5’ terminal modification is triazolyl phosphonate. In particular embodiments, the 5’ phosphate modification at the 5’ terminal nucleotide 10 . In exemplary embodiments, the guide strand comprises one or more non-negatively charged internucleotidic linkages in the Rp or the Sp configuration between the +4 nucleotide, relative to the 5’ terminal nucleotide, and the +10 nucleotide, relative to the 5’ terminal nucleotide, the +11 nucleotide, relative to the 5’ terminal nucleotide, and the N-2 nucleotide, 15 relative to the 3’ terminal nucleotide, or combinations thereof. In exemplary embodiments, the guide strand comprises at least one 2’ sugar moiety modification (e.g., a 2’-methoxy (2’-OMe) or 2’-fluoro (2’-F) sugar moiety modification). In particular embodiments, the guide strand comprises a 2’ sugar moiety modification. In certain embodiments, the guide strand comprises a 2’-F sugar moiety modification of the 3’ 20 nucleotide of a nucleotide pair linked by a non-negatively charged internucleotidic linkage. In particular embodiments, the guide strand comprises seven contiguous 2’-OMe sugar moiety modifications (e.g., at the +17 to +23 nucleotides, relative to the 5’ terminal nucleotide). In certain embodiments, the guide strand comprises six 2’-F sugar moiety modifications (e.g., at the +2, +4, +6, +11, +14, and +16 nucleotides, relative to the 5’ terminal nucleotide). In certain 25 embodiments, the guide strand comprises four 2’-OMe sugar moiety modifications at the +7 to 15 088290.0189 +10 nucleotides, relative to the 5’terminal nucleotide, a 2’-OMe sugar moiety modification at the +3 nucleotide, relative to the 5’ terminal nucleotide, two 2’-OMe sugar moiety modifications at the +12 and +13 nucleotides, relative to the 5’ terminal nucleotide, a 2’-OMe sugar moiety modification at the +15 nucleotide, relative to the 5’ terminal nucleotide, or 5 combinations thereof. In certain embodiments, the guide strand comprises a 2’ sugar moiety modification pattern of: 5’-m[fl2r]m[fl2r]m[fl2r]mmmm[fl2r]mm[fl2r]m[fl2r]mmmmmmm -3’ wherein: m represents a 2’-OMe sugar moiety modification; and 10 [fl2r] represents a 2’-F sugar moiety modification. In certain embodiments, the guide strand comprises an internucleotidic linkage modification pattern of: 5’-mPS[fl2r]PSmPN[fl2r]POmPO[fl2r]POmPOmPOmPOmPN[fl2r]POmPOmPO [fl2r]POmPO[fl2r]POmPOmPOmPOmPOmPSmPSm-3’ 15 wherein: PS represents a phosphorothioate internucleotidic linkage; PN represents a phosphoryl guanidine internucleotidic linkage; and PO represents a phosphodiester or phosphate internucleotidic linkage. In certain embodiments, the phosphorothioate internucleotidic linkage between the 5’ terminal 20 (+1) nucleotide and the immediately downstream (+2) nucleotide of the guide strand is in the Sp configuration. In particular embodiments, the phosphorothioate internucleotidic linkage between the +2 nucleotide and the immediately downstream (+3) nucleotide of the guide strand is in the Rp configuration. In exemplary embodiments, the passenger strand comprises at least one 2’ sugar moiety 25 modification (e.g., a 2’-methoxy (2’-OMe) or 2’-fluoro (2’-F) sugar moiety modification). In exemplary embodiments, the passenger strand comprises three contiguous 2’-F sugar moiety modifications and 10 contiguous 2’-OMe sugar moiety modifications. In exemplary embodiments, the passenger strand comprises four 2’-F sugar moiety modifications at the +7, +9, +10, and +11 nucleotides, relative to the 5’ terminal nucleotide. In certain embodiments, 30 the passenger strand comprises six 2’-OMe sugar moiety modifications at the +1 to +6 nucleotides, relative to the 5’ terminal nucleotide, one 2’-OMe sugar moiety modification at the +8 nucleotide, relative to the 5’ terminal nucleotide, ten 2’-OMe sugar moiety modifications a the +12 to +21 nucleotides, relative to the 5’ terminal nucleotide, or combinations thereof. In particular embodiments, passenger strand comprises a 2’ sugar moiety modification pattern of: 16 088290.0189 5’-mmmmmm[fl2r]m[fl2r][fl2r][fl2r]mmmmmmmmmm-3’ wherein: m represents a 2’-OMe internucleotidic linkage; and [fl2r] represents a 2’-F internucleotidic linkage. 5 In certain embodiments, the passenger strand comprises an internucleotidic linkage modification pattern of: 5’-mPSmPOmPOmPOmPOmPO[fl2r]POmPO[fl2r]PO[fl2r]PO[fl2r]POmPO mPOmPOmPOmPOmPOmPOmPOmPSm-3’ wherein: 10 PS represents a phosphorothioate internucleotidic linkage; and PO represents a phosphodiester or phosphate internucleotidic linkage. In particular embodiments, each phosphorothioate internucleotidic linkage is independently in the Sp configuration. In exemplary embodiments, the non-negatively charged internucleotidic linkage has a15 neutral charge, e.g., the non-negatively charged internucleotidic linkage i ,where n and m are each independently 0-49, e.g. the non-negatively charged internucleotidic linkage i . In exemplary embodiments, the carbohydrate moiety is a mono-GalNAc, a bis-GalNAc, a tri-GalNAc, a mannose derivative, a galactose derivative, a glucose sugar derivative, other 20 saccharide derivatives or combinations thereof. In particular embodiments, the carbohydrate moiety is a tri-GalNAc (GalNAc3). In exemplary embodiments, the carbohydrate moiety is connected at a nucleoside or an internucleotidic linkage through a linker (e.g., C12oyl) where a GalNAc3 linked to C12oyl (GalNAc3C12oyl) is 17 088290.0189 . exemplary embodiments, the carbohydrate moiety is connected at the end of the 5’ end of the passenger strand. In exemplary embodiments, the guide strand and the passenger strand each 5 independently have a length of 20-25 nucleotides. In a second aspect, the invention relates to a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, where the guide strand comprises at least 15 contiguous nucleotides differing by: 10 i. no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAG GAUU-3’, ii. no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAG GAUU-3’, iii. no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGA AGGA-3’, or iv. no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAA GGA-3’, the guide strand comprises 2’ sugar moiety and internucleotidic modification patterns of: 15 5’-mPS[fl2r]PSmPN[fl2r]POmPO[fl2r]POmPOmPOmPOmPN[fl2r]POmPOmPO [fl2r]POmPO[fl2r]POmPOmPOmPOmPOmPSmPSm-3’, and the passenger strand comprises 2’ sugar moiety and internucleotidic modification patterns of: 5’-mPSmPOmPOmPOmPOmPO[fl2r]POmPO[fl2r]PO[fl2r]PO[fl2r]POmPO 20 mPOmPOmPOmPOmPOmPOmPOmPSm-3’; wherein: PS represents a phosphorothioate internucleotidic linkage, PN represents a phosphoryl guanidine internucleotidic linkage, and PO represents a phosphodiester or phosphate internucleotidic linkage, 18 088290.0189 Where the guide strand comprises a 5’ phosphate modification at the 5’ terminal nucleotide thereof, where the 5’ phosphate modification passenger strand comprises a carbohydrate moiety, wherein the carbohydrate moiety is a tri- GalNAc (GalNAc3) at the 5’-end of the passenger strand. 5 In exemplary embodiments, the guide strand comprises one or more of a phosphorothioate internucleotidic linkage between the +1 and +2 nucleotides, relative to the 5’ terminal nucleotide, in the Sp configuration, a phosphorothioate internucleotidic linkage between the +2 and +3 nucleotides, relative to the 5’ terminal nucleotide, in the Rp configuration, a phosphoryl guanidine internucleotidic linkage between the +3 and +4 10 nucleotides, relative to the 5’ terminal nucleotide, in the Sp configuration, and a phosphoryl guanidine internucleotidic linkage between the +10 and +11 nucleotides, relative to the 5’ terminal nucleotide, in the Rp configuration. In exemplary embodiments, the passenger strand comprises phosphorothioate internucleotidic linkages between the +1 and +2 nucleotide, relative to the 5’ terminal nucleotide, in the Sp configuration, and between the N and N-1 15 nucleotides, relative to the 3’ terminal nucleotide, in the Sp configuration. In exemplary embodiments, the carbohydrate moiety is connected at the 5’ end of the passenger strand through a C12oyl linker and wherein a GalNAc3 linked to C12oyl (GalNAc3C12oyl) is . 20 In exemplary embodiments, the phosphoryl guanidine internucleotidic linkage is . 19 088290.0189 In a third aspect, the invention relates to a composition comprising the dsRNAi agent comprising a second agent, wherein the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine 5 reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an 10 Lp(a) inhibitor; an LPL activator; and combinations thereof. In a fourth aspect, the invention relates to a method for preventing or treating an INHBE-related disorder in a subject in need thereof, comprising administering to the subject the dsRNAi agent. In exemplary embodiments, the prevention or treatment of an INHBE-related disorder 15 is selected from: improving glucose control; increasing lean body mass; reducing fat mass; treating obesity, e.g., abdominal obesity; treating diabetes, e.g., type 2 diabetes; treating insulin resistance; coronary artery disease; treating chronic kidney disease; treating liver issues associated with increased fat mass, obesity, and / or diabetes; treating a metabolic disorder; treating an elevated triglyceride level; treating a lipodystrophy; treating liver inflammation; 20 treating fatty liver disease; treating hypercholesterolemia; treating an elevated liver enzyme; treating nonalcoholic steatohepatitis (NASH); treating a cardiovascular disease; treating cardiomyopathy; treating high blood pressure; treating heart failure; and inducing lipolysis (fat- burning) while preserving muscle mass. In exemplary embodiments, administering to the subject the dsRNAi agent prior to, 25 concurrently with, and / or after performing bariatric surgery on the subject and / or administering a second agent to the subject, where the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor 30 (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof. 20 088290.0189 In exemplary embodiments, the second agent is a GLP-1 receptor agonist (GLP-1 agonist), e.g., exenatide, dulaglutide, liraglutide, tirzepatide, and semaglutide, e.g., semaglutide. In exemplary embodiments, the dsRNAi agent and the second agent of any of claims 48-51 (the second agent) are administered to the subject concurrently. In exemplary 5 embodiments, the dsRNAi agent and the second agent are administered to the subject sequentially. In exemplary embodiments, the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent continues upon said administration of the dsRNAi agent is administered to the subject. In exemplary embodiments, the second agent is administered before the dsRNAi agent is 10 administered to the subject, and wherein said administration of the second agent terminates upon said administration of the dsRNAi agent is administered to the subject. In exemplary embodiments, the second agent is administered to the subject daily. In exemplary embodiments, the amount of the second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent. 15 In exemplary embodiments, bariatric surgery is performed on the subject before the dsRNAi agent is administered to the subject. In exemplary embodiments, the dsRNAi agent is administered every six months after the subject has been administered the second agent or has undergone said bariatric surgery. In exemplary embodiments, the dsRNAi agent is administered annually after the subject has been administered the second agent or has 20 undergone said bariatric surgery. In exemplary embodiments, the subject loses substantially more body weight compared to when the subject is administered the second agent alone. In particular embodiments, the subject loses double the body weight. In exemplary embodiments, the subject does not undergo rebound body weight gain which is expected when the subject is administered the second agent 25 alone. In exemplary embodiments, the dsRNAi agent is administered every six months or annually. In exemplary embodiments, the dsRNAi agent is administered subcutaneously. In exemplary embodiments, the subject maintains at least 50%, 60%, 75%, 90%, or 95% of its pre-administration skeletal muscle mass. In exemplary embodiments, the subject loses the body 30 weight without loss of muscle mass or without substantial loss of muscle mass. In exemplary embodiments, the loss of the body weight is accompanied by a reduction in fat mass, e.g., a reduction in visceral fat mass. In exemplary embodiments, the effects on the subject’s muscle mass and fat mass are consistent with the protective effects of heterozygous INHBE loss-of- function (LoF) mutations. In exemplary embodiments, a healthy metabolic profile of the 21 088290.0189 subject is maintained. In exemplary embodiments, the subject is administered the second agent (e.g., GLP-1 agonist) in a dosage amount that is the same as or lower than a standard dosage amount. In exemplary embodiments, infiltration of activated macrophages in visceral adipose is decreased. In exemplary embodiments, infiltration of activated macrophages in visceral 5 adipose is decreased by at least 50%. In exemplary embodiments, the decreased infiltration of activated macrophages in visceral adipose is associated with treating type 2 diabetes and / or coronary artery disease where the treating type 2 diabetes and / or coronary artery disease are secondary to obesity. In a fifth aspect, the invention relates to the dsRNAi agent for use in preventing or 10 treating an INHBE-related disorder in a subject in need thereof. In exemplary embodiments, the dsRNAi agent for use in preventing or treating an INHBE-related disorder in a subject in need thereof further comprises a second agent, wherein the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and15 norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin- 4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an 20 Lp(a) inhibitor; an LPL activator; and combinations thereof. In exemplary embodiments, the prevention or treatment of an INHBE-related disorder is selected from: improving glucose control; increasing lean body mass; reducing fat mass; treating obesity, e.g., abdominal obesity; treating diabetes, e.g., type 2 diabetes; treating insulin resistance; coronary artery disease; treating chronic kidney disease; treating liver issues 25 associated with increased fat mass, obesity, and / or diabetes; treating a metabolic disorder; treating an elevated triglyceride level; treating a lipodystrophy; treating liver inflammation; treating fatty liver disease; treating hypercholesterolemia; treating an elevated liver enzyme; treating nonalcoholic steatohepatitis (NASH); treating a cardiovascular disease; treating cardiomyopathy; treating high blood pressure; treating heart failure; and inducing lipolysis (fat- 30 burning) while preserving muscle mass. In exemplary embodiments, the dsRNAi agent for use in preventing or treating an INHBE-related disorder in a subject in need thereof comprises administering to the subject the dsRNAi agent prior to, concurrently with, and / or after bariatric surgery on the subject, and / or administering a second agent to the subject, where the second agent is selected from: a gastric 22 088290.0189 and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin- 4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; 5 sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof. In exemplary embodiments, the second agent is a GLP-1 receptor agonist (GLP-1 10 agonist), e.g., exenatide, dulaglutide, liraglutide, tirzepatide, and semaglutide, e.g., semaglutide. In exemplary embodiments, the dsRNAi agent and the second agent of any of claims 48-51 (the second agent) are administered to the subject concurrently. In exemplary embodiments, the dsRNAi agent and the second agent are administered to the subject sequentially. In exemplary embodiments, the second agent is administered before the dsRNAi 15 agent is administered to the subject, and wherein said administration of the second agent continues upon said administration of the dsRNAi agent is administered to the subject. In exemplary embodiments, the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent terminates upon said administration of the dsRNAi agent is administered to the subject. In exemplary 20 embodiments, the second agent is administered to the subject daily. In exemplary embodiments, the amount of the second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent. In exemplary embodiments, bariatric surgery is performed on the subject before the dsRNAi agent is administered to the subject. In exemplary embodiments, the dsRNAi agent is 25 administered every six months after the subject has been administered the second agent or has undergone said bariatric surgery. In exemplary embodiments, the dsRNAi agent is administered annually after the subject has been administered the second agent or has undergone said bariatric surgery. In exemplary embodiments, the subject loses substantially more body weight compared 30 to when the subject is administered the second agent alone. In particular embodiments, the subject loses double the body weight. In exemplary embodiments, the subject does not undergo rebound body weight gain which is expected when the subject is administered the second agent alone. 23 088290.0189 In exemplary embodiments, the dsRNAi agent is administered every six months or annually. In exemplary embodiments, the dsRNAi agent is administered subcutaneously. In exemplary embodiments, the subject maintains at least 50%, 60%, 75%, 90%, or 95% of its pre-administration skeletal muscle mass. In exemplary embodiments, the subject loses the body 5 weight without loss of muscle mass or without substantial loss of muscle mass. In exemplary embodiments, the loss of the body weight is accompanied by a reduction in fat mass, e.g., a reduction in visceral fat mass. In exemplary embodiments, the effects on the subject’s muscle mass and fat mass are consistent with the protective effects of heterozygous INHBE loss-of- function (LoF) mutations. In exemplary embodiments, a healthy metabolic profile of the 10 subject is maintained. In exemplary embodiments, the subject is administered the second agent (e.g., GLP-1 agonist) in a dosage amount that is the same as or lower than a standard dosage amount. In exemplary embodiments, infiltration of activated macrophages in visceral adipose is decreased. In exemplary embodiments, infiltration of activated macrophages in visceral adipose is decreased by at least 50%. In exemplary embodiments, the decreased infiltration of 15 activated macrophages in visceral adipose is associated with treating type 2 diabetes and / or coronary artery disease where the treating type 2 diabetes and / or coronary artery disease are secondary to obesity. In certain embodiments, the present disclosure is directed to methods for improving glucose control in a subject in need thereof, comprising administering to the subject a double- 20 stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; 25 iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 24 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for increasing lean body mass in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 25 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for reducing fat mass in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 26 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating obesity in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 27 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating insulin resistance in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 28 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating coronary artery disease in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 29 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating chronic kidney disease in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 30 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating liver issues associated with increased fat mass, obesity, and / or diabetes in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous 20 nucleotides differing by: i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, 25 wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 31 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating a metabolic disorder in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 32 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating an elevated triglyceride level in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 33 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating a lipodystrophy in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 34 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating liver inflammation in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 35 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating fatty liver disease in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 36 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating hypercholesterolemia in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 37 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating an elevated liver enzyme in a subject in need thereof, comprising administering to the a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 38 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating nonalcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)- specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 39 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 40 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating a cardiomyopathy in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 41 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating high blood pressure in a subject in need thereof, comprising administering to the subject a double- stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 42 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 In certain embodiments, the present disclosure is directed to methods for treating heart failure in a subject in need thereof, comprising administering to the subject a double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)-specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein the guide strand comprises at least 15 contiguous nucleotides differing by: 20 i) no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGAUU-3’; ii) no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAGGAUU-3’; iii) no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGAAGGA-3’; or iv) no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’, wherein the guide strand comprises: i) a non-negatively charged internucleotidic linkage (e.g., 25 the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged 43 088290.0189 internucleotidic linkage the Rp configuration between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate 5 internucleotidic linkage in the Sp configuration between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide, wherein the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and ii) a phosphorothioate internucleotidic10 linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N- 1) nucleotide, wherein the guide strand and the passenger strand each independently has a length of 15-49 nucleotides (e.g., 20-25 nucleotides), and wherein the dsRNAi agent comprises a carbohydrate moiety (e.g., a tri-GalNAc linked to, e.g., C12oyl) connected at a nucleoside or an internucleotidic linkage, e.g., at the 5’ end of the passenger strand. 15 Unless otherwise noted, all sequences (including, but not limited to base sequences and patterns of chemistry, modification, and / or stereochemistry) are presented in 5’ to 3’ order, with the 5’ terminal nucleotide identified as the “+1” position and the 3’ terminal nucleotide identified either by the number of nucleotides of the full sequence or by “N”, with the penultimate nucleotide identified, e.g., as “N-1”, and so on. 20 In certain embodiments, the present disclosure provides compositions and methods related to an oligonucleotide which is specific to an INHBE target and which has any format, structural element or base sequence of any oligonucleotide disclosed herein. In certain embodiments, the present disclosure provides compositions and methods related to an oligonucleotide which is specific to an INHBE target and which has or comprises 25 the base sequence of any oligonucleotide disclosed herein, or a region of at least 15 contiguous nucleotides of the base sequence of any oligonucleotide disclosed herein, wherein the first nucleotide of the base sequence or the first nucleotide of the at least 15 contiguous nucleotides can be optionally replaced by T or DNA T. In certain embodiments, the present disclosure provides compositions and methods for 30 RNA interference directed by a RNAi agent (also referred to as a RNAi oligonucleotides). In certain embodiments, oligonucleotides of such compositions can have a format, structural 44 088290.0189 element or base sequence of an oligonucleotide disclosed herein. In certain embodiments, the present disclosure provides compositions and methods for RNase H-mediated knockdown of an INHBE target gene RNA directed by an oligonucleotide (e.g., an antisense oligonucleotide). 5 Provided oligonucleotides and oligonucleotide compositions can have any format, structural element or base sequence of any oligonucleotide disclosed herein. In certain embodiments, a structural element is a 5’-end structure, 5’-end region, 5’-nucleotide, seed region, post-seed region, 3’-end region, 3’-terminal dinucleotide, 3’-end cap, or any portion of any of these structures, GC content, long GC stretch, and / or any modification, chemistry, 10 stereochemistry, pattern of modification, chemistry or stereochemistry, or a chemical moiety (e.g., including but not limited to, a targeting moiety, a lipid moiety, a GalNAc moiety, a carbohydrate moiety, etc.), any component, or any combination of any of the above. In certain embodiments, the present disclosure provides compositions and methods of use of an oligonucleotide. 15 In certain embodiments, an oligonucleotide directing a particular event or activity participates in the particular event or activity, e.g., a decrease in the expression, level or activity of a target gene or a gene product thereof. In certain embodiments, an oligonucleotide is deemed to “direct” a particular event or activity when presence of the oligonucleotide in a system in which the event or activity can occur correlates with increased detectable incidence, 20 frequency, intensity and / or level of the event or activity. In certain embodiments, a provided oligonucleotide comprises any one or more structural elements of an oligonucleotide as described herein, e.g., a base sequence (or a portion thereof of at least 15 contiguous bases); a pattern of internucleotidic linkages (or a portion thereof of at least 5 contiguous internucleotidic linkage); a pattern of stereochemistry of 25 internucleotidic linkages (or a portion thereof of at least 5 contiguous internucleotidic linkages); a 5’-end structure; a 5’-end region; a first region; a second region; and a 3’-end region (which can be a 3’-terminal dinucleotide and / or a 3’-end cap); and an optional additional chemical moiety; and, in certain embodiments, at least one structural element comprises a chirally controlled chiral center. In certain embodiments, a 3’-terminal dinucleotide can 30 comprise two total nucleotides. In certain embodiments, an oligonucleotide further comprises a chemical moiety selected from, as non-limiting examples, a targeting moiety, a carbohydrate moiety, a GalNAc moiety, a lipid moiety, and any other chemical moiety described herein or known in the art. In certain embodiments, a moiety that binds APGR is a moiety of GalNAc, or a variant, derivative or modified version thereof, as described herein and / or known in the 45 088290.0189 art. In certain embodiments, an oligonucleotide is a RNAi agent. In certain embodiments, a first region is a seed region. In certain embodiments, a second region is a post-seed region. In certain embodiments, a provided oligonucleotide comprises any one or more structural elements of a RNAi agent as described herein, e.g., a 5’-end structure; a 5’-end 5 region; a seed region; a post-seed region (the region between the seed region and the 3’-end region); and a 3’-end region (which can be a 3’-terminal dinucleotide and / or a 3’-end cap); and an optional additional chemical moiety; and, in certain embodiments, at least one structural element comprises a chirally controlled chiral center. In certain embodiments, a 3’-terminal dinucleotide can comprise two total nucleotides. In certain embodiments, an oligonucleotide 10 further comprises a chemical moiety selected from, as non-limiting examples, a targeting moiety, a carbohydrate moiety, a GalNAc moiety, and a lipid moiety. In certain embodiments, a moiety that binds APGR is any GalNAc, or variant, derivative or modification thereof, as described herein or known in the art. In certain embodiments, a provided oligonucleotide comprises any one or more 15 structural elements of an oligonucleotide as described herein, e.g., a 5’-end structure, a 5’-end region, a first region, a second region, a 3’-end region, and an optional additional chemical moiety, wherein at least one structural element comprises a chirally controlled chiral center. In certain embodiments, the oligonucleotide comprises a span of at least 5 total nucleotides without 2’-modifications. In certain embodiments, the oligonucleotide further comprises an 20 additional chemical moiety selected from, as non-limiting examples, a targeting moiety, a carbohydrate moiety, a GalNAc moiety, and a lipid moiety. In certain embodiments, a provided oligonucleotide is capable of directing RNA interference. In certain embodiments, a provided oligonucleotide is capable of directing RNase H-mediated knockdown. In certain embodiments, a provided oligonucleotide is capable of directing both RNA interference and 25 RNase H-mediated knockdown. In certain embodiments, a first region is a seed region. In certain embodiments, a second region is a post-seed region. In certain embodiments, a nucleotide is a natural nucleotide. In certain embodiments, a nucleotide is a modified nucleotide. In certain embodiments, a nucleotide is a nucleotide analog. In certain embodiments, a base is a modified base. In certain embodiments, a base is 30 protected nucleobase, such as a protected nucleobase used in oligonucleotide synthesis. In certain embodiments, a base is a base analog. In certain embodiments, a sugar is a modified sugar. In certain embodiments, a sugar is a sugar analog. In certain embodiments, an internucleotidic linkage is a modified internucleotidic linkage. In certain embodiments, a nucleotide comprises a base, a sugar, and an internucleotidic linkage, wherein each of the base, 46 088290.0189 the sugar, and the internucleotidic linkage is independently and optionally naturally-occurring or non-naturally occurring. In certain embodiments, a nucleoside comprises a base and a sugar, wherein each of the base and the sugar is independently and optionally naturally-occurring or non-naturally occurring. Non-limiting examples of nucleotides include DNA (2’-deoxy) and 5 RNA (2’-OH) nucleotides; and those which comprise one or more modifications at the base, sugar and / or internucleotidic linkage. Non-limiting examples of sugars include ribose and deoxyribose; and ribose and deoxyribose with 2’-modifications, including but not limited to 2’-F, LNA, 2’-OMe, and 2’-MOE modifications. In certain embodiments, an internucleotidic linkage is a moiety which does not a comprise a phosphorus but serves to link two natural or 10 non-natural sugars. In certain embodiments, a composition comprises a multimer of two or more of any: oligonucleotides of a first plurality and / or oligonucleotides of a second plurality, wherein the oligonucleotides of the first and second plurality can independently direct knockdown of the same or different targets independently via RNA interference and / or RNase H-mediated 15 knockdown. In certain embodiments, the present disclosure provides an oligonucleotide composition comprising a first plurality of oligonucleotides which share: 1) a common base sequence; 2) a common pattern of backbone linkages; 20 3) common stereochemistry independently at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, or 50 chiral internucleotidic linkages (“chirally controlled internucleotidic linkages”); which composition is chirally controlled in that level of the first plurality of oligonucleotides in the composition is predetermined. 25 Among other things, the present disclosure encompasses the recognition that stereorandom oligonucleotide preparations contain a plurality of distinct chemical entities that differ from one another, e.g., in the stereochemical structure (or stereochemistry) of individual backbone chiral centers within the oligonucleotide chain. Without control of stereochemistry of backbone chiral centers, stereorandom oligonucleotide preparations provide uncontrolled 30 compositions comprising undetermined levels of oligonucleotide stereoisomers. Even though these stereoisomers may have the same base sequence and / or chemical modifications, they are different chemical entities at least due to their different backbone stereochemistry, and they can have, as demonstrated herein, different properties, e.g., sensitivity to nucleases, activities, distribution, etc. In certain embodiments, a particular stereoisomer may be defined, for 47 088290.0189 example, by its base sequence, its length, its pattern of backbone linkages, and its pattern of backbone chiral centers. In certain embodiments, the present disclosure demonstrates that improvements in properties and activities achieved through control of stereochemistry within an oligonucleotide can be comparable to, or even better than those achieved through use of 5 chemical modification In some embodiments, a ds oligonucleotide targeting INHBE or ds oligonucleotide targeting INHBE composition is useful for prevention or treatment of a INHBE-associated condition, disorder, or disease, in a subject in need thereof. In some embodiments, the present disclosure provides a method for preventing or treating a INHBE-associated condition, 10 disorder, or disease, comprising administering to a subject suffering therefrom or subject thereto a therapeutically effective amount of a provided ds oligonucleotide or a pharmaceutical composition that can deliver or comprise a therapeutically effective amount of a provided ds oligonucleotide. In some embodiments, the present disclosure provides pharmaceutical compositions which comprise a provided ds oligonucleotide targeting INHBE and a 15 pharmaceutically acceptable carrier. In some embodiments, oligonucleotides in a pharmaceutical composition are in one or more pharmaceutically acceptable salt forms, e.g., a sodium salt form, an ammonium salt form, etc. In some embodiments, the present disclosure provides a method for preventing or treating a INHBE-associated condition by administering a dsRNAi composition. 20 In some embodiments, an oligonucleotide or oligonucleotide composition is useful for the manufacture of a medicament for prevention or treatment of a INHBE-associated condition, disorder, or disease, such as metabolic disorders, e.g., metabolic syndrome, and related diseases, e.g., obesity, cardiovascular disease, diabetes, and hypertension, in a subject in need thereof. 25 Various INHBE-associated conditions, disorders, or diseases may be prevented and / or treated utilizing provided technologies (e.g., oligonucleotide, compositions, methods, etc.). In some embodiments, a condition, disorder, or disease is a metabolic disorder, e.g., metabolic syndrome, or related disease, e.g., obesity, cardiovascular disease, diabetes, or hypertension. In some embodiments, the present disclosure provides a method for decreasing 30 infiltration of activated macrophages in visceral adipose, e.g., by at least 50%, e.g., up to 68% compared to PBS treatment, in a subject in need thereof, comprising: administering to the subject an effective amount of the dsRNAi agent of the present disclosure. In some embodiments, the subject is suffering from type 2 diabetes and / or coronary artery disease. In 48 088290.0189 some embodiments, said type 2 diabetes and / or coronary artery disease is / are secondary to obesity. BRIEF DESCRPTION OF THE DRAWINGS Figure 1 depicts evaluation of an exemplary siRNA of the present disclosure plus 5 semaglutide on the body weight in the groups of mice as described in Example 8. Figures 2A-2B Figure 2A depicts evaluation of an exemplary siRNA of the presentdisclosure on the body weight in the groups of mice as described in Example 9. Tissue weights (white adipose tissues, quadriceps, tibialis anterior, and the gastrocnemius) are depicted in Figure 2B. 10 Figures 3 and 4 depict evaluation of an exemplary siRNA of the present disclosure plus semaglutide on the body weight in the groups of mice as described in Example 11 (Groups Nos.1, 2 and 6 in Figure 3; Group No.5 in Figure 4). Figure 5 depicts evaluation of an exemplary siRNA of the present disclosure on the body weight in the groups of mice as described in Example 7. 15 Figure 6 depicts evaluation of an exemplary siRNA of the present disclosure on the body weight in the groups of mice as described in Example 14. Figure 7 depicts evaluation of an exemplary siRNA of the present disclosure on chronic inflammation in epididymal white adipose tissue as described in Example 10. Data are means ± SEM of 4-5 mice. Each dot represents an individual mouse. One-way ANOVA with Tukey 20 multiple comparison test. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments. 25 Definitions As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", 30 Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. As used herein, the terms, “analog”, “antisense”, “chiral control”, “chirally controlled oligonucleotide composition”, “chirally controlled nucleic acid composition”, 49 088290.0189 “internucleotidic linkage”, “in vitro”, “in vivo”, “linkage phosphorus”, “linker”, “linkingmoiety”, “modified nucleobase”, “modified base”, “modified nucleoside”, “modified nucleotide”, “modified sugar”, “nucleic acid”, “nucleobase”, “nucleoside”, “nucleotide” “oligonucleotide”, “oligonucleotide type”, “substituted,” “optionally substituted”, “oral 5 administration”, “administered orally”, “parenteral administration”, “administered parenterally”, “partially unsaturated”, “pharmaceutical composition”, “pharmaceutically acceptable”, “pharmaceutically acceptable carrier”, “pharmaceutically acceptable salt”, “protecting group”, “sample”, “subject”, “test subject”, “substantially”, “sugar”, “susceptible to”, “therapeutic agent”, “therapeutically effective amount”, “treat,” “treatment,” “treating”, 10 “unsaturated”, “wild-type” have their art-understood meaning as would be appreciated by those of ordinary skill in the art, and as specifically defined in WO 2024 / 182749, at pages 147-179, the contents of which are incorporated herein by reference in their entirety. As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds (e.g., ds oligonucleotides) generally also apply to 15 pharmaceutically acceptable salts of such compounds. INHBE In some embodiments, INHBE refers to a gene or a gene product thereof (including but not limited to, a nucleic acid, including but not limited to a DNA or RNA, a transcript, a protein encoded thereby; can be from any form of INHBE, e.g., wide-type or mutant alleles) from any 20 species. In some embodiments, it refers to the gene and product thereof in human. In some embodiments, it refers to the gene and product thereof in a non-human primate. Various INHBE sequences, including variants thereof, from human, mouse, rat, monkey, etc., are readily available to those of skill in the art. In some embodiments, INHBE is a human or mouse INHBE, which is wild-type or mutant. It has been reported that INHBE can have a number of 25 functions. Various technologies, e.g., assays, cells, animal models, etc., have also been reported and can be utilized for characterization and / or assessment of provided technologies (e.g., oligonucleotides, compositions, methods, etc.) in accordance with the present disclosure. In some embodiments, a INHBE gene, transcript (e.g., mRNA before or after splicing), or protein variant or isoform comprises a mutation. In some embodiments, a INHBE gene, 30 transcript or protein is or a transcription or translation product of an alternatively spliced variant or isoform. INHBE-Associated Conditions, disorders, or diseases 50 088290.0189 Various conditions, disorders, or diseases are reported to be associated with INHBE. Generally, a disease, disorder, or condition is associated with ttINHBE if the presence, level, activity, and / or form of INHBE and / or products (e.g.d, transcripts, encoded proteins, etc.) thereof correlates with incidence of and / or susceptibility to the disease, disorder, or condition 5 (e.g., across a relevant population). In some embodiments, a condition, disorder, or disease associated with INHBE may be treated and / or prevented by reducing expression, level and / or activity of INHBE transcripts and / or proteins. Various INHBE-associated conditions, disorders, or diseases are reported. In some embodiments, an INHBE-associated condition, disorder, or disease is that finds use in 10 connection with the compositions and methods disclosed herein include, but are not limited to: improving glucose control; increasing lean body mass; reducing fat mass; a metabolic disorder; diabetes, e.g., type 2 diabetes; insulin resistance; obesity; elevated triglyceride level; lipodystrophy; liver inflammation; fatty liver disease; hypercholesterolemia; an elevated liver enzyme; nonalcoholic steatohepatitis (NASH); a cardiovascular disease; coronary artery 15 disease; cardiomyopathy; high blood pressure; heart failure; chronic kidney disease; and liver issues associated with increased fat mass, obesity, and / or diabetes. Among other things, provided technologies are useful for treating or preventing a condition, disorder, or disease associated with INHBE, including, but not limited to, improving glucose control; increasing lean body mass; reducing fat mass; obesity, e.g., abdominal obesity; 20 a metabolic disorder; diabetes, e.g., type 2 diabetes; insulin resistance; coronary artery disease; chronic kidney disease; elevated triglyceride level; lipodystrophy; liver inflammation; fatty liver disease; hypercholesterolemia; an elevated liver enzyme; nonalcoholic steatohepatitis (NASH); a cardiovascular disease; coronary artery disease; cardiomyopathy; high blood pressure; heart failure; chronic kidney disease; inducing lipolysis (fat-burning) while 25 preserving muscle mass; and liver issues associated with increased fat mass, obesity, and / or diabetes. In some embodiments, treatment or prevention with provided technologies reduces rate of INHBE production and reduces or halts or reverses accumulation of INHBE. In some embodiments, treatment or prevention with provided technologies increases the rate of weight 30 loss or otherwise allows for control of body weight. As appreciated by those skilled in the art, mechanisms, genotypes, symptoms, biomarkers, etc. of such conditions, disorders, or diseases may be utilized in accordance with the present disclosure to characterize / assess provided technologies. 51 088290.0189 Double Stranded Oligonucleotides As examples, certain ds oligonucleotides targeting INHBE comprising certain example base sequences, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus 5 stereochemistry and patterns thereof, linkers, and / or additional chemical moieties are presented in Table 1, below. Among other things, oligonucleotides, e.g., those in Table 1, may be utilized to target a INHBE transcript, e.g., to reduce the level of a INHBE transcript and / or a product thereof. In certain exemplary embodiments, the ds oligonucleotide targeting INHBE of the 10 present disclosure comprises the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of: DSR-0104068, DSR-0104099, DSR-0104072, DSR-0104075, DSR-0104083, DSR- 0104091, and DSR-0104071. In certain exemplary embodiments, a ds oligonucleotide targeting 15 INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of: DSR-0104068, DSR-0104099, DSR-0104072, DSR-0104075, DSR-0104083, DSR-0104091, and DSR-0104071. In certain exemplary embodiments, a ds 20 oligonucleotide targeting INHBE of the present disclosure comprises a passenger strand comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104068. In certain exemplary embodiments, a ds oligonucleotide targeting INHBE 25 of the present disclosure comprises a guide strand comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties DSR-0104068, DSR-0104099, DSR-0104072, DSR- 0104075, DSR-0104083, DSR-0104091, and DSR-0104071comprising the base sequence, 30 nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104068. In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar 52 088290.0189 modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104068 comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof. 5 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104099. 10 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104072. 15 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104075. 20 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104083. 25 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104091. 30 In certain exemplary embodiments, a ds oligonucleotide targeting INHBE of the present disclosure comprising the base sequence, nucleobase modifications and patterns thereof, sugar modifications and patterns thereof, internucleotidic linkages and patterns thereof, linkage phosphorus stereochemistry and patterns thereof, linkers, and / or additional chemical moieties of DSR-0104071. 53 088290.0189 Table 1. Example Double Stranded Oligonucleotides Targeting INHBE 54 088290.0189 55 088290.0189 56 088290.0189 57 088290.0189 58 088290.0189 59 088290.0189 60 088290.0189 Table 1A. Examples of Guide Sequences Targeting INHBE 61 088290.0189 62 088290.0189 63 088290.0189 64 088290.0189 65 088290.0189 66 088290.0189 67 088290.0189 68 088290.0189 69 088290.0189 70 088290.0189 71 088290.0189 72 088290.0189 73 088290.0189 74 088290.0189 75 088290.0189 76 088290.0189 77 088290.0189 78 088290.0189 79 088290.0189 80 088290.0189 81 088290.0189 82 088290.0189 83 088290.0189 84 088290.0189 85 088290.0189 86 088290.0189 87 088290.0189 Table 1B. Examples of Passenger Sequences Targeting INHBE 88 088290.0189 89 088290.0189 90 088290.0189 91 088290.0189 92 088290.0189 93 088290.0189 94 088290.0189 95 088290.0189 96 088290.0189 97 088290.0189 98 088290.0189 99 088290.0189 100 088290.0189 101 088290.0189 102 088290.0189 103 088290.0189 104 088290.0189 105 088290.0189 106 088290.0189 107 088290.0189 108 088290.0189 109 088290.0189 110 088290.0189 111 088290.0189 112 088290.0189 113 088290.0189 114 088290.0189 115 088290.0189 116 088290.0189 117 088290.0189 118 088290.0189 119 088290.0189 120 088290.0189 121 088290.0189 122 088290.0189 123 088290.0189 124 088290.0189 125 088290.0189 Table 1C 126 088290.0189 127 088290.0189 128 088290.0189 129 088290.0189 130 088290.0189 131 088290.0189 132 088290.0189 Table 1D 133 088290.0189 134 088290.0189 135 088290.0189 136 088290.0189 137 088290.0189 138 088290.0189 139 088290.0189 140 088290.0189 Notes: HELM notations, due to their length, may be divided into multiple lines in Table 1 (e.g., Tables 1A, 1B, and 1C). As appreciated by those skilled in the art, nucleoside units are 5 unmodified unless otherwise indicated (e.g., with m, [fl2r], etc.); linkages, unless otherwise indicated, are natural phosphate linkages; and acidic / basic groups may independently exist in their salts. If an internucleotidic linkage is not specified, the internucleotidic linkage is a natural phosphate linkage. A natural DNA sugar may also be indicated with “d” as in d(G), d(A), d(C), d(T), etc., and a natural phosphate linkage may be indicated with “p” in Table 1. 141 088290.0189 Oligonucleotides in Table 1 are described using various features of Hierarchical Editing Language for Macromolecules (HELM), which is described in, e.g., Zhang, T. et al. J Chem Inf Model. 2012 Oct 22;52(10):2796-806 and Milton, J. et al. J Chem Inf Model. 2017 Jun 26;57(6):1233-1239, which are incorporated herein by reference. As described in Zhang et al., 5 2012 and Milton et al., 2017, connections between oligonucleotides, linker moieties, GalNAc moieties, etc. may be indicated in HELM, for example, as the following: CHEM1,RNA1,1:R1- 1:R1, wherein CHEM1 is, e.g., a first linker or moiety, RNA1 is an oligonucleotide, and 1:R1- 1:R1 indicates that CHEM1 is linked via a first attachment point to a first attachment point on a first monomer of RNA1, as described herein (see, e.g., below). A double-stranded 10 oligonucleotide may be indicated in HELM, for example, as the following: RNA1, wherein RNA1 is, e.g., a first oligonucleotide strand of a double-stranded oligonucleotide, and RNA2, wherein RNA2 is, e.g., a second oligonucleotide strand of the double-stranded oligonucleotide. Various moieties and modifications (e.g., internucleotidic linkages, sugars, nucleobases, etc.) are described in the present disclosure including the below: 15 m: 2’-OMe or 2-O-methylribose; [fl2r]: 2’-F or 2-fluororibose; PO or p: phosphodiester or phosphate; PS or [sp]: phosphorothioate; Rp or [Rsp]: phosphorothioate in the Rp configuration; 20 Sp or [Ssp]: phosphorothioate or phosphoryl guanidine in the Sp configuration; -dimethylimidazolidin-2-ylidene)phosphoramidate); [n001R]: n001 in Rp configuration; [n001S]: n001 in Sp configuration; -dimethylimidazolidin-2-ylidene)phosphoramidate); 25 [n003R]: n003 in Rp configuration; [n003S]: n003 in Sp configuration; 142 088290.0189 (di(morpholin-1-yl)methylene)phosphoramidate); [n008R]: n008 in Rp configuration; [n008S]: n008 in Sp configuration; docecyl-3-methylimidazolidin-2- 5 ylidene)phosphoramidate); [n009R]: n009 in Rp configuration; [n009S]: n009 in Sp configuration; -dimethyltetrahydropyrimidin-2(1H)-ylidene)phosphoramidate); [n025R]: n025 in Rp configuration; 10 [n025S]: n025 in Sp configuration; dimethylamino-butyl)-3-methylimidazolidin-2- ylidene)phosphoramidate); [n029R]: n029 in Rp configuration; [n029S]: n029 in Sp configuration; 15 -hexyl-3-methylimidazolidin-2- ylidene)phosphoramidate); [n031R]: n031 in Rp configuration; 143 088290.0189 [n031S]: n031 in Sp configuration; -hexadecyl-3- methylimidazolidin-2-ylidene)phosphoramidate); [n033R]: n033in Rp configuration; 5 [n033S]: n033 in Sp configuration; -dihexylimidazolidin-2- ylidene)phosphoramidate); [n037R]: n037in Rp configuration; [n037S]: n037 in Sp configuration; 10 didodecylimidazolidin-2-ylidene)phosphoramidate); [n039R]: n039 in Rp configuration; [n039S]: n039 in Sp configuration; 15 (1,3-dihexadecylimidazolidin-2-ylidene)phosphoramidate); [n040R]: n040in Rp configuration; [n040S]: n040 in Sp configuration; 144 088290.0189 -methoxyethyl)imidazolidin-2- ylidene)phosphoramidate); [n043R]: n043 in Rp configuration; [n043S]: n043 in Sp configuration; 5 -pent-2-en-1-yl]imidazolidin-2- ylidene)phosphoramidate); [n046R]: n046in Rp configuration; [n046S]: n046 in Sp configuration; -pent-2-en-1-yl]imidazolidin-2- 10 ylidene)phosphoramidate); [n047R]: n047in Rp configuration; [n047S]: n047 in Sp configuration; -dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2- ylidene)phosphoramidate); 15 [n065R]: n065 in Rp configuration; [n065S]: n065 in Sp configuration; 145 088290.0189 aminopropyl)-3-methylimidazolidin-2- ylidene)phosphoramidate); [n069R]: n069 in Rp configuration; [n069S]: n069 in Sp configuration; 5 benzo[d]imidazol- 2ylidene)phosphoramidate); [n070R]: n070 in Rp configuration; [n070S]: n070 in Sp configuration; benzo[d]imidazol- 10 2ylidene)phosphoramidate); [n071R]: n071 in Rp configuration; [n071S]: n071 in Sp configuration; [n076R]: n076in Rp configuration; 15 [n076S]: n076 in Sp configuration; 146 088290.0189 dimethylimidazolidin-2-ylidene)phosphoramidate); [n077R]: n077in Rp configuration; [n077S]: n077 in Sp configuration; 5 (disub phosphoryl)-1-decyl-3- methylimidazolidin-2-imine); [n082R]: n082in Rp configuration; [n082S]: n082 in Sp configuration; (disub phosphoryl)-1- 10 tetradecyl-3-methylimidazolidin-2-imine); [n083R]: n083in Rp configuration; [n083S]: n083 in Sp configuration; (disub phosphoryl)- 1-octadecyl-3-methylimidazolidin-2-imine); 15 [n084R]: n084in Rp configuration; [n084S]: n084 in Sp configuration; 147 088290.0189 linoleic acid); [n086R]: n086 in Rp configuration; [n086S]: n086 in Sp configuration; 5 hexyldecanoic acid; [n087R]: n087 in Rp configuration); [n087S]: n087 in Sp configuration; oleic acid); 10 [n088R]: n088 in Rp configuration; [n088S]: n088 in Sp configuration; (1-(3-stearamidopropyl)-methyl-3-methylimidazolidin-2-ylidene)phosphoramidate); [n089R]: n089 in Rp configuration; 15 [n089S]: n089 in Sp configuration; 148 088290.0189 (N-(1-(3-palmitoleamidopropyl)-methyl-3-methylimidazolidin-2-ylidene)phosphoramidate); [n090R]: n090 in Rp configuration; [n090S]: n090 in Sp configuration; 5 palmitamidopropyl)-methyl-3-methylimidazolidin-2-ylidene)phosphoramidate); [n091R]: n091 in Rp configuration; [n091S]: n091 in Sp configuration; 10 (N-(1-(3-turbinaramidopropyl)-methyl-3-methylimidazolidin-2-ylidene)phosphoramid); [n092R]: n092 in Rp configuration; [n092S]: n092 in Sp configuration; [ptz]: , (1H-1,2,3-triazol-4-yl)phosphonate or 4-phosphono-1,2,3-triazol-1- yl, bonded to 5’-carbon of the 5’-end nucleoside; 15 [d5m]: 5’-deoxy-2'-O-methylribose; [Rm5d5m]: 5’-(R)-methyl-5’-deoxy-2’-O-methylribose; [vped5m]: 5’-(E)-vinylphosphonate-5’-deoxy-2’-O-methylribose; [GalNAc3C12oyl]: triantennary GalNAc with C12 linker or 149 088290.0189 [GalNAc3C12oyl][nC6o] conjugated to the 5’-end of an oligonucleotide: 5 = oligonucleotide chain [nC6o]: −NH−(CH2)6− linker (C6 linker, C6 amine linker or C6 amino linker), connected to one moiety, e.g., CHEM2 (e.g., [GalNAc3C12oyl]), through −NH− (e.g., forming an amide group –C(O)−NH−), and, in various cases, the 5’-end of the oligonucleotide chain through a linkage (e.g., if the 5’-end of an oligonucleotide contains p, through a phosphate linkage (the 10 end −CH2− bonded to an oxygen atom which is bonded to linkage phosphorus); if the 5’-end of an oligonucleotide contains [sp], through a phosphorothioate linkage (the end −CH2− bonded 150 088290.0189 to an oxygen atom which is bonded to linkage phosphorus). [nC6o] may also be properly considered as 6-aminohexanol wherein, as indicated, its amino group forms an amide and its hydroxy forms a linkage such as a phosphate linkage. 5 Double Stranded Oligonucleotide Lengths As appreciated by those skilled in the art, ds oligonucleotides targeting INHBE can be of various lengths to provide desired properties and / or activities for various uses. Many technologies for assessing, selecting and / or optimizing oligonucleotide length are available in the art and can be utilized in accordance with the present disclosure. As demonstrated herein, 10 in many embodiments, ds oligonucleotides targeting INHBE are of suitable lengths to hybridize with their targets and reduce levels of their targets and / or an encoded product thereof. In some embodiments, an oligonucleotide is long enough to recognize a target nucleic acid (e.g., a INHBE mRNA). In some embodiments, an oligonucleotide is sufficiently long to distinguish between a target nucleic acid and other nucleic acids (e.g., a nucleic acid having a base 15 sequence which is not INHBE) to reduce off-target effects. In some embodiments, a ds oligonucleotide targeting INHBE is sufficiently short to reduce complexity of manufacture or production and to reduce cost of products. Double Stranded Oligonucleotide Internucleotidic Linkages In some embodiments, ds oligonucleotides targeting INHBE comprise base 20 modifications, sugar modifications, and / or internucleotidic linkage modifications. Various internucleotidic linkages can be utilized in accordance with the present disclosure to link units comprising nucleobases, e.g., nucleosides. In some embodiments, ds oligonucleotides targeting INHBE comprise both one or more modified internucleotidic linkages and one or more natural phosphate linkages. As widely known by those skilled in the art, natural 25 phosphate linkages are widely found in natural DNA and RNA molecules; they have the structure of −OP(O)(OH)O−, connect sugars in the nucleosides in DNA and RNA, and may be in various salt forms, for example, at physiological pH (about 7.4), natural phosphate linkages are predominantly exist in salt forms with the anion being −OP(O)(O−)O−. A modified internucleotidic linkage, or a non-natural phosphate linkage, is an internucleotidic linkage that 30 is not natural phosphate linkage or a salt form thereof. Modified internucleotidic linkages, depending on their structures, may also be in their salt forms. For example, as appreciated by those skilled in the art, phosphorothioate internucleotidic linkages which have the structure of −OP(O)(SH)O− may be in various salt forms, e.g., at physiological pH (about 7.4) with the 151 088290.0189 anion being −OP(O)(S−)O−. Without wishing to be bound by any particular theory, the present disclosure notes that a neutral internucleotidic linkage can be more hydrophobic than a phosphorothioate 5 internucleotidic linkage (PS), which can be more hydrophobic than a natural phosphate linkage (PO). Typically, unlike a PS or PO, a neutral internucleotidic linkage bears less charge. Without wishing to be bound by any particular theory, the present disclosure notes that incorporation of one or more neutral internucleotidic linkages into a ds oligonucleotide may increase the ds oligonucleotides’ ability to be taken up by a cell and / or to escape from 10 endosomes. Without wishing to be bound by any particular theory, the present disclosure notes that incorporation of one or more neutral internucleotidic linkages can be utilized to modulate melting temperature of duplexes formed between a ds oligonucleotide and its target nucleic acid. Without wishing to be bound by any particular theory, the present disclosure notes that 15 incorporation of one or more non-negatively charged internucleotidic linkages, e.g., neutral internucleotidic linkages, into a ds oligonucleotide may be able to increase the ds oligonucleotide’s ability to mediate a function such as target adenosine editing. As appreciated by those skilled in the art, many other types of internucleotidic linkages may be utilized in accordance with the present disclosure, for example, those described in U.S. 20 Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,177,195; 5,023,243; 5,034,506; 5,166,315; 5,185,444; 5,188,897; 5,214,134; 5,216,141; 5,235,033; 5,264,423; 5,264,564; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,938; 5,405,939; 5,434,257; 5,453,496; 5,455,233; 5,466,677; 5,466,677; 5,470,967; 5,476,925; 5,489,677; 5,519,126; 5,536,821; 5,541,307; 5,541,316; 5,550,111; 5,561,225; 5,563,253; 5,571,799; 5,587,361; 5,596,086; 25 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,625,050; 5,633,360; 5,663,312; 5,677,437; 5,677,439; 6,160,109; 6,239,265; 6,028,188; 6,124,445; 6,169,170; 6,172,209; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; or RE39464. In certain embodiments, a modified internucleotidic linkage is one described in US 9982257, 30 US 20170037399, US 20180216108, WO 2017192664, WO 2017015575, WO2017062862, WO 2018067973, WO 2017160741, WO 2017192679, WO 2017210647, WO 2018098264, PCT / US18 / 35687, PCT / US18 / 38835, or PCT / US18 / 51398, the nucleobases, sugars, 152 088290.0189 internucleotidic linkages, chiral auxiliaries / reagents, and technologies for oligonucleotide synthesis (reagents, conditions, cycles, etc.) of each of which is independently incorporated herein by reference. In certain embodiments, a ds oligonucleotide comprises one or more internucleotidic 5 linkages that improve one or more pharmaceutical properties and / or activities of the oligonucleotide. It is well documented in the art that certain oligonucleotides are rapidly degraded by nucleases and exhibit poor cellular uptake through the cytoplasmic cell membrane (Poijarvi-Virta et al., Curr. Med. Chem. (2006), 13(28);3441-65; Wagner et al., Med. Res. Rev. (2000), 20(6):417-51; Peyrottes et al., Mini Rev. Med. Chem. (2004), 4(4):395-408; Gosselin 10 et al., (1996), 43(1):196-208; Bologna et al., (2002), Antisense & Nucleic Acid Drug Development 12:33-41). Vives et al. (Nucleic Acids Research (1999), 27(20):4071-76) reported that tert-butyl SATE pro-oligonucleotides displayed markedly increased cellular penetration compared to the parent oligonucleotide under certain conditions. Various types of internucleotidic linkages may be utilized in combination of other 15 structural elements, e.g., sugars, to achieve desired ds oligonucleotide properties and / or activities. For example, the present disclosure routinely utilizes modified internucleotidic linkages and modified sugars, optionally with natural phosphate linkages and natural sugars, in designing ds oligonucleotides. In certain embodiments, the present disclosure provides a ds oligonucleotide comprising one or more modified sugars. In certain embodiments, the present 20 disclosure provides a ds oligonucleotide comprising one or more modified sugars and one or more modified internucleotidic linkages, one or more of which are natural phosphate linkages. Double Stranded Oligonucleotide Compositions Among other things, the present disclosure provides various ds oligonucleotide compositions. In some embodiments, the present disclosure provides ds oligonucleotide 25 compositions of ds oligonucleotides described herein. In some embodiments, a ds oligonucleotide composition, e.g., a ds oligonucleotide targeting INHBE composition, comprises a plurality of an oligonucleotide described in the present disclosure. In some embodiments, a ds oligonucleotide composition, e.g., a ds oligonucleotide targeting INHBE composition, is chirally controlled. In some embodiments, a ds oligonucleotide composition, 30 e.g., a ds oligonucleotide targeting INHBE composition, is not chirally controlled (stereorandom). In some embodiments, the present disclosure encompasses technologies for designing and preparing chirally controlled ds oligonucleotide compositions. In some embodiments, a 153 088290.0189 chirally controlled ds oligonucleotide composition comprises a controlled / pre-determined (not random as in stereorandom compositions) level of a plurality of ds oligonucleotides, wherein the ds oligonucleotides share the same linkage phosphorus stereochemistry at one or more chiral internucleotidic linkages (chirally controlled internucleotidic linkages). In some 5 embodiments, ds oligonucleotides of a plurality share the same pattern of backbone chiral centers (stereochemistry of linkage phosphorus). In some embodiments, a pattern of backbone chiral centers is as described in the present disclosure. In some embodiments, ds oligonucleotides of a plurality share a common constitution. In some embodiments, they are structurally identical. 10 For example, in some embodiments, the present disclosure provides a ds oligonucleotide composition comprising a plurality of ds oligonucleotides, wherein oligonucleotides of the plurality share: 1) a common base sequence, and 2) the same linkage phosphorus stereochemistry independently at one or more (e.g., 15 about 1-50, 1-40, 1-30, 1-25, 1-20, 1-15, 1-10, 5-50, 5-40, 5-30, 5-25, 5-20, 5-15, 5-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 or more) chiral internucleotidic linkages (“chirally controlled internucleotidic linkages”); wherein level of ds oligonucleotides of the plurality in the composition is non-random (e.g., controlled / pre-determined as described herein). 20 Common patterns of backbone chiral centers, as appreciated by those skilled in the art, comprise at least one Rp or at least one Sp. Certain patterns of backbone chiral centers are illustrated in, e.g., Table 1. In some embodiments, a chirally controlled ds oligonucleotide composition is enriched, 25 relative to a substantially racemic preparation of ds oligonucleotides share the same common base sequence and a common pattern of backbone linkages, for oligonucleotides of the particular ds oligonucleotide type. In some embodiments, ds oligonucleotides of a plurality, e.g., a particular ds oligonucleotide type, have a common pattern of backbone phosphorus modifications and a 30 common pattern of nucleoside modifications. In some embodiments, ds oligonucleotides of a plurality have a common pattern of sugar modifications. In some embodiments, ds oligonucleotides of a plurality have a common pattern of base modifications. In some embodiments, ds oligonucleotides of a plurality have a common pattern of nucleoside modifications. In some embodiments, ds oligonucleotides of a plurality have the same 154 088290.0189 constitution. In many embodiments, ds oligonucleotides of a plurality are identical. In some embodiments, ds oligonucleotides of a plurality are of the same oligonucleotide (as those skilled in the art will appreciate, such ds oligonucleotides may each independently exist in one of the various forms of the ds oligonucleotide, and may be the same, or different forms of the 5 oligonucleotide). In some embodiments, ds oligonucleotides of a plurality are each independently of the same ds oligonucleotide or a pharmaceutically acceptable salt thereof. In some embodiments, a chirally controlled oligonucleotide composition is chirally pure (or stereopure, stereochemically pure) oligonucleotide composition, wherein the 10 oligonucleotide composition comprises a plurality of oligonucleotides, wherein the oligonucleotides are independently of the same stereoisomer [including that each chiral element of the oligonucleotides, including each chiral linkage phosphorus, is independently defined (stereodefined)]. A chirally pure (or stereopure, stereochemically pure) oligonucleotide composition of an oligonucleotide stereoisomer does not contain other 15 stereoisomers (as appreciated by those skilled in the art, one or more unintended stereoisomers may exist as impurities from, e.g., preparation, storage, etc.). Chirally controlled oligonucleotide compositions can demonstrate a number of advantages over stereorandom oligonucleotide compositions. Among other things, chirally controlled oligonucleotide compositions are more uniform than corresponding stereorandom 20 oligonucleotide compositions with respect to oligonucleotide structures. By controlling stereochemistry, compositions of individual stereoisomers can be prepared and assessed, so that chirally controlled oligonucleotide composition of stereoisomers with desired properties and / or activities can be developed. In some embodiments, chirally controlled oligonucleotide compositions provides better delivery, stability, clearance, activity, selectivity, and / or toxicity 25 profiles compared to, e.g., corresponding stereorandom oligonucleotide compositions. In some embodiments, chirally controlled oligonucleotide compositions provide better efficacy, fewer side effects, and / or more convenient and effective dosage regimens. Among other things, patterns of backbone chiral centers as described herein can be utilized to provide controlled cleavage of oligonucleotide targets (e.g., transcripts such as pre-mRNA, mature mRNA, etc.; 30 including control of cleavage sites, rate and / or extent of cleavage at cleavage sites, and / or overall rate and extent of cleavage, etc.). In some embodiments, oligonucleotides in provided compositions, e.g., chirally controlled oligonucleotide compositions, are ds oligonucleotides targeting INHBE as described herein. 155 088290.0189 In some embodiments, the present disclosure provides a stereorandom oligonucleotide composition, e.g., a stereorandom ds oligonucleotide targeting INHBE composition. In some embodiments, the present disclosure provides a stereorandom ds oligonucleotide targeting INHBE composition which is capable of decreasing the level, activity or expression of a 5 INHBE gene or a gene product thereof. In some embodiments, the present disclosure provides a stereorandom ds oligonucleotide targeting INHBE composition which is capable of decreasing the level, activity or expression of a INHBE gene or a gene product thereof, and wherein the base sequence of the ds oligonucleotides targeting INHBE is, comprises, or comprises a span (e.g., at least 10 or 15 contiguous bases) of a base sequence disclosed herein 10 (e.g., a base sequence in Table 1, wherein each T may be independently replaced with U and vice versa). In some embodiments, an oligonucleotide composition comprises one or more internucleotidic linkages which are stereocontrolled (chirally controlled; in some embodiments, stereopure) and one or more internucleotidic linkages which are stereorandom. 15 In some embodiments, a ds oligonucleotide targeting INHBE composition comprises one or more internucleotidic linkages which are stereocontrolled (chirally controlled; in some embodiments, stereopure) and one or more internucleotidic linkages which are stereorandom. In some embodiments, an oligonucleotide composition comprises one or more internucleotidic linkages which are stereocontrolled (e.g., chirally controlled or stereopure) and 20 one or more internucleotidic linkages which are stereorandom. Such oligonucleotides may target various targets and may have various base sequences, and may be capable of operating via one or more of various modalities (e.g., RNase H mechanism, steric hindrance, double- or single-stranded RNA interference, exon skipping modulation, CRISPR, aptamer, etc.). In some embodiments, the present disclosure provides a chirally controlled 25 oligonucleotide composition, e.g., chirally controlled ds oligonucleotide targeting INHBE composition. In some embodiments, provided chirally controlled oligonucleotide compositions comprise a plurality of oligonucleotides, e.g., ds oligonucleotides targeting INHBE, of the same constitution, and have one or more internucleotidic linkages. In some embodiments, a plurality of oligonucleotides, e.g., in a chirally controlled oligonucleotide 30 composition, is a plurality of an oligonucleotide selected from Table 1, wherein the oligonucleotide comprises at least one Rp or Sp linkage phosphorus in a chirally controlled internucleotidic linkage. In some embodiments, a plurality of oligonucleotides, e.g., in a chirally controlled oligonucleotide composition, is a plurality of an oligonucleotide selected from Table 1, wherein each phosphorothioate internucleotidic linkage in the oligonucleotide is 156 088290.0189 independently chirally controlled (each phosphorothioate internucleotidic linkage is independently Rp or Sp). In some embodiments, an oligonucleotide composition, e.g., a ds oligonucleotide targeting INHBE composition is a substantially pure preparation of a single oligonucleotide in that oligonucleotides in the composition that are not the single 5 oligonucleotide are impurities from the preparation process of the single oligonucleotide, in some case, after certain purification procedures. In some embodiments, a single oligonucleotide is an oligonucleotide of Table 1, wherein each chiral internucleotidic linkage of the oligonucleotide is chirally controlled (e.g., indicated as S or R but not X in “Stereochemistry / Linkage”). 10 In some embodiments, a chirally controlled oligonucleotide composition can have, relative to a corresponding stereorandom oligonucleotide composition, increased activity and / or stability, increased delivery, and / or decreased ability to elicit adverse effects such as complement, TLR9 activation, etc. In some embodiments, a stereorandom (non-chirally controlled) oligonucleotide composition differs from a chirally controlled oligonucleotide 15 composition in that its corresponding plurality of oligonucleotides do not contain any chirally controlled internucleotidic linkages but the stereorandom oligonucleotide composition is otherwise identical to the chirally controlled oligonucleotide composition. In some embodiments, the present disclosure pertains to a chirally controlled ds oligonucleotide targeting INHBE composition which is capable of decreasing the level, activity 20 or expression of a INHBE gene or a gene product thereof. In some embodiments, the present disclosure provides a chirally controlled ds oligonucleotide targeting INHBE composition which is capable of decreasing the level, activity or expression of a INHBE gene or a gene product thereof, and comprises a plurality of oligonucleotides which share a common base sequence that is or comprises a base sequence 25 disclosed herein (e.g., in Table 1, wherein each T may be independently replaced with U and vice versa). In some embodiments, a provided chirally controlled oligonucleotide composition is a chirally controlled ds oligonucleotide targeting INHBE composition comprising a plurality of ds oligonucleotides targeting INHBE. In some embodiments, a chirally controlled 30 oligonucleotide composition is a chirally pure (or “stereochemically pure”) oligonucleotide composition. In some embodiments, the present disclosure provides a chirally pure oligonucleotide composition of an oligonucleotide in Table 1, wherein each chiral internucleotidic linkage of the oligonucleotide is independently chirally controlled (Rp or Sp, e.g., R or S but not X in “Stereochemistry / Linkage”). As one of ordinary skill in the art will 157 088290.0189 understand, chemical selectivity rarely, if ever, achieves completeness (absolute 100%). In some embodiments, a chirally pure oligonucleotide composition comprises a plurality of oligonucleotides, wherein oligonucleotides of the plurality are structurally identical and all have the same structure (the same stereoisomeric form; in the context of oligonucleotide, 5 typically the same diastereomeric form as typically multiple chiral centers exist in an oligonucleotide), and the chirally pure oligonucleotide composition does not contain any other stereoisomers (in the context of oligonucleotide, typically diastereomers as typically multiple chiral centers exist in an oligonucleotide; to the extent, e.g., achievable by stereoselective preparation). As appreciated by those skilled in the art, stereorandom (or “racemic”, “non- 10 chirally controlled”) oligonucleotide compositions are random mixtures of many stereoisomers (e.g., 2ndiastereoisomers wherein n is the number of chiral linkage phosphorus for oligonucleotides in which other chiral centers (e.g., carbon chiral centers in sugars) are chirally controlled each independently existing in one configuration and only chiral linkage phosphorus centers are not chirally controlled). 15 Certain data showing properties and / or activities of chirally controlled oligonucleotide composition, e.g., chirally controlled ds oligonucleotide targeting INHBE compositions in decreasing the level, activity and / or expression of a INHBE target gene or a gene product thereof, are shown in, for example, the Examples section of this document. In some embodiments, the present disclosure provides an oligonucleotide composition 20 comprising oligonucleotides that comprise at least one chiral linkage phosphorus. In some embodiments, the present disclosure provides a ds oligonucleotide targeting INHBE composition comprising ds oligonucleotides targeting INHBE that comprise at least one chiral linkage phosphorus. In some embodiments, the present disclosure provides a ds oligonucleotide targeting INHBE composition in which the ds oligonucleotides targeting 25 INHBE comprise a chirally controlled phosphorothioate internucleotidic linkage, wherein the linkage phosphorus has a Rp configuration. In some embodiments, the present disclosure provides a ds oligonucleotide targeting INHBE composition in which the ds oligonucleotides targeting INHBE comprise a chirally controlled phosphorothioate internucleotidic linkage, wherein the linkage phosphorus has a Sp configuration. 30 In some embodiments, compared to reference oligonucleotide compositions, provided chirally controlled oligonucleotide compositions (e.g., chirally controlled ds oligonucleotide targeting INHBE compositions) are surprisingly effective. In some embodiments, desired biological effects (e.g., as measured by decreased levels of mRNA, proteins, etc. whose levels are targeted for reduction) can be enhanced by more than 5, 10, 15, 20, 25, 30, 40, 50, or 100 158 088290.0189 fold (e.g., as measured by remaining levels of mRNA, proteins, etc.). In some embodiments, a change is measured by decrease of an undesired mRNA level compared to a reference condition. In some embodiments, a change is measured by increase of a desired mRNA level compared to a reference condition. In some embodiments, a change is measured by decrease 5 of an undesired mRNA level compared to a reference condition. In some embodiments, a reference condition is absence of treatment, e.g., by a chirally controlled oligonucleotide composition. In some embodiments, a reference condition is a corresponding stereorandom composition of oligonucleotides having the same constitution. In some embodiments, the present disclosure provides a chirally controlled 10 oligonucleotide composition, e.g., a chirally controlled ds oligonucleotide targeting INHBE composition, wherein the linkage phosphorus of at least one chirally controlled internucleotidic linkage is Sp. In some embodiments, the present disclosure provides a chirally controlled oligonucleotide composition, e.g., a chirally controlled ds oligonucleotide targeting INHBE composition, wherein the majority of linkage phosphorus of chirally controlled internucleotidic15 linkages are Sp. In some embodiments, about 50%-100%, 55%-100%, 60%-100%, 65%- 100%, 70%-100%, 75%-100%, 80%-100%, 85%-100%, 90%-100%, 55%-95%, 60%-95%, 65%-95%, or about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99% or more, of all chirally controlled phosphorothioate internucleotidic linkages are Sp. In some embodiments, about 50%-100%, 55%-100%, 60%-100%, 65%-100%, 70%-100%, 75%- 20 100%, 80%-100%, 85%-100%, 90%-100%, 55%-95%, 60%-95%, 65%-95%, or about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99% or more, of all phosphorothioate internucleotidic linkages are chirally controlled and are Sp. In some embodiments, about 50%- 100%, 55%-100%, 60%-100%, 65%-100%, 70%-100%, 75%-100%, 80%-100%, 85%-100%, 90%-100%, 55%-95%, 60%-95%, 65%-95%, or about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 25 90%, 95%, 97%, 99% or more, of all chirally controlled internucleotidic linkages (or of all chiral internucleotidic linkages, or of all internucleotidic linkages) are Sp. In some embodiments, the present disclosure provides a chirally controlled oligonucleotide composition, e.g., a chirally controlled ds oligonucleotide targeting INHBE composition, wherein the majority of chiral internucleotidic linkages are chirally controlled and are Sp at 30 their linkage phosphorus. In some embodiments, the present disclosure provides a chirally controlled oligonucleotide composition, e.g., a chirally controlled ds oligonucleotide targeting INHBE composition, wherein each chiral internucleotidic linkage is chirally controlled and each chiral linkage phosphorus is Sp. In some embodiments, the present disclosure provides a 159 088290.0189 chirally controlled oligonucleotide composition, e.g., chirally controlled ds oligonucleotide targeting INHBE composition, wherein at least one chirally controlled internucleotidic linkage has a Rp linkage phosphorus. In some embodiments, the present disclosure provides a chirally controlled oligonucleotide composition, e.g., a chirally controlled ds oligonucleotide targeting 5 INHBE composition, wherein at least one chirally controlled internucleotidic linkage comprises a Rp linkage phosphorus and at least one chirally controlled internucleotidic linkage comprises a Sp linkage phosphorus. In some embodiments, at least one phosphorothioate internucleotidic linkage is chirally controlled and Rp. In some embodiments, about 1-5, e.g., about 1, 2, 3, 4, or 5 phosphorothioate internucleotidic linkage is chirally controlled and Rp. 10 In some embodiments, about 50%-100%, 55%-100%, 60%-100%, 65%-100%, 70%-100%, 75%-100%, 80%-100%, 85%-100%, 90%-100%, 55%-95%, 60%-95%, 65%-95%, or about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99% or more, of all chirally controlled non-negatively charged internucleotidic linkages (e.g., n001) are Rp. In some embodiments, each chirally controlled n001 is Rp. 15 Sugars Various sugars, including modified sugars, can be utilized in accordance with the present disclosure. In some embodiments, the present disclosure provides sugar modifications and patterns thereof optionally in combination with other structural elements (e.g., internucleotidic linkage modifications and patterns thereof, pattern of backbone chiral centers 20 thereof, etc.) that when incorporated into oligonucleotides can provide improved properties and / or activities. The most common naturally occurring nucleosides comprise ribose sugars (e.g., in RNA) or deoxyribose sugars (e.g., in DNA) linked to the nucleobases adenosine (A), cytosine (C), guanine (G), thymine (T) or uracil (U). In some embodiments, a sugar, e.g., various sugars 25 in many oligonucleotides in Table 1 (unless otherwise notes), is a natural DNA sugar (in DNA nucleic acids or oligonucleotides, having the structure of , wherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions are connected to internucleotidic linkages (as appreciated by those skilled in the art, if at the 5’-end of an oligonucleotide, the 5’ position may be connected to a 5’-end group (e.g., −OH), and if at the 3’-end of an 30 oligonucleotide, the 3’ position may be connected to a 3’-end group (e.g., −OH). In some embodiments, a sugar is a natural RNA sugar (in RNA nucleic acids or oligonucleotides, having 160 088290.0189 the structure , wherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions are connected to internucleotidic linkages (as appreciated by those skilled in the art, if at the 5’-end of an oligonucleotide, the 5’ position may be connected to a 5’-end group (e.g., −OH), and if at the 3’-end of an oligonucleotide, the 3’ position may be connected 5 to a 3’-end group (e.g., −OH). In some embodiments, a sugar is a modified sugar in that it is not a natural DNA sugar or a natural RNA sugar. Among other things, modified sugars may provide improved stability. In some embodiments, modified sugars can be utilized to alter and / or optimize one or more hybridization characteristics. In some embodiments, modified sugars can be utilized to alter and / or optimize target recognition. In some embodiments, 10 modified sugars can be utilized to optimize Tm. In some embodiments, modified sugars can be utilized to improve oligonucleotide activities. Sugars can be bonded to internucleotidic linkages at various positions. As non-limiting examples, internucleotidic linkages can be bonded to the 2’, 3’, 4’ or 5’ positions of sugars. In some embodiments, as most commonly in natural nucleic acids, an internucleotidic linkage 15 connects with one sugar at the 5’ position and another sugar at the 3’ position unless otherwise indicated. In some embodiments, a sugar is an optionally substituted natural DNA or RNA sugar. In some embodiments, a sugar is optionally substituted . In some embodiments, the 2’ position is optionally substituted. In some embodiments, a sugar . 20 some embodiments, a sugar has the structure , wherein each of R1s, R2s, R3s, R4s, and R5sis independently −H, a suitable substituent or suitable sugar modification (e.g., those described in US 9394333, US 9744183, US 9605019, US 9982257, US 20170037399, US 20180216108, US 20180216107, US 9598458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, 25 WO 2018 / 022473, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 161 088290.0189 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 032612, and / or WO 2020 / 191252, the substituents, sugar modifications, descriptions of R1s, R2s, R3s, R4s, and R5s, and modified sugars of each of which are independently incorporated herein by reference). In some embodiments, a sugar has the structure . In some 5 embodiments, R4sis −H. In some embodiments, a sugar has the structure , wherein R2sis −H, halogen, or −OR, wherein R is optionally substituted C1-6aliphatic. In some embodiments, R2sis −H. In some embodiments, R2sis −F. In some embodiments, R2sis −OMe. In some embodiments, R2sis −OCH2CH2OMe. Various additional sugars useful for preparing oligonucleotides or analogs thereof are 10 known in the art and may be utilized in accordance with the present disclosure. Nucleobases Various nucleobases may be utilized in provided oligonucleotides in accordance with the present disclosure. In some embodiments, a nucleobase is a natural nucleobase, the most commonly occurring ones being A, T, C, G and U. In some embodiments, a nucleobase is a 15 modified nucleobase in that it is not A, T, C, G or U. In some embodiments, a nucleobase is optionally substituted A, T, C, G or U, or a substituted tautomer of A T, C, G or U. In some embodiments, a nucleobase is optionally substituted A, T, C, G or U, e.g., 5mC, 5- hydroxymethyl C, etc. In some embodiments, a nucleobase is alkyl-substituted A, T, C, G or U. In some embodiments, a nucleobase is A. In some embodiments, a nucleobase is T. In 20 some embodiments, a nucleobase is C. In some embodiments, a nucleobase is G. In some embodiments, a nucleobase is U. In some embodiments, a nucleobase is 5mC. In some embodiments, a nucleobase is substituted A, T, C, G or U. In some embodiments, a nucleobase is a substituted tautomer of A, T, C, G or U. In some embodiments, substitution protects certain functional groups in nucleobases to minimize undesired reactions during oligonucleotide 25 synthesis. Suitable technologies for nucleobase protection in oligonucleotide synthesis are widely known in the art and may be utilized in accordance with the present disclosure. In some embodiments, modified nucleobases improves properties and / or activities of oligonucleotides. For example, in many cases, 5mC may be utilized in place of C to modulate certain undesired 162 088290.0189 biological effects, e.g., immune responses. In some embodiments, when determining sequence identity, a substituted nucleobase having the same hydrogen-bonding pattern is treated as the same as the unsubstituted nucleobase, e.g., 5mC may be treated the same as C [e.g., an oligonucleotide having 5mC in place of C (e.g., AT5mCG) is considered to have the same base 5 sequence as an oligonucleotide having C at the corresponding location(s) (e.g., ATCG)]. In some embodiments, a modified nucleobase is a modified nucleobase known in the art, e.g., WO2017 / 210647. In some embodiments, modified nucleobases are expanded-size nucleobases in which one or more aryl and / or heteroaryl rings, such as phenyl rings, have been added. 10 In some embodiments, a nucleobase is one described in US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 15 2019 / 217784, WO 2019 / 032612, and / or WO 2020 / 191252, the nucleobases of each of which is incorporated herein by reference. Additional Chemical Moieties In some embodiments, a ds oligonucleotide targeting INHBE comprises one or more additional chemical moieties. Various additional chemical moieties, e.g., targeting moieties, 20 carbohydrate moieties, lipid moieties, etc. are known in the art and can be utilized in accordance with the present disclosure to modulate properties and / or activities of ds oligonucleotides targeting INHBE, e.g., stability, half life, activities, delivery, pharmacodynamics properties, pharmacokinetic properties, etc. In some embodiments, certain additional chemical moieties facilitate delivery of oligonucleotides to desired cells, tissues and / or organs, including but not 25 limited the cells of the central nervous system. In some embodiments, certain additional chemical moieties facilitate internalization of oligonucleotides. In some embodiments, certain additional chemical moieties increase oligonucleotide stability. In some embodiments, the present disclosure provides technologies for incorporating various additional chemical moieties into oligonucleotides. 30 In certain embodiments, a ds oligonucleotide comprises an additional chemical moiety demonstrates increased delivery to and / or activity in a tissue compared to a reference oligonucleotide, e.g., a reference oligonucleotide which does not have the additional chemical moiety but is otherwise identical. 163 088290.0189 In certain embodiments, non-limiting examples of additional chemical moieties include carbohydrate moieties, targeting moieties, etc., which, when incorporated into oligonucleotides, can improve one or more properties. In certain embodiments, an additional chemical moiety is selected from: glucose, GluNAc (N-acetyl amine glucosamine) and 5 anisamide moieties. In certain embodiments, a provided ds oligonucleotide can comprise two or more additional chemical moieties, wherein the additional chemical moieties are identical or non-identical, or are of the same category (e.g., carbohydrate moiety, sugar moiety, targeting moiety, etc.) or not of the same category. In certain embodiments, an additional chemical moiety is a targeting moiety. In certain 10 embodiments, an additional chemical moiety is or comprises a carbohydrate moiety. In certain embodiments, an additional chemical moiety is or comprises a lipid moiety. In certain embodiments, an additional chemical moiety is or comprises a ligand moiety for, e.g., cell receptors such as a sigma receptor, an asialoglycoprotein receptor, etc. In certain embodiments, a ligand moiety is or comprises an anisamide moiety, which may be a ligand moiety for a sigma 15 receptor. In certain embodiments, a ligand moiety is or comprises a GalNAc moiety, which may be a ligand moiety for an asialoglycoprotein receptor. In certain embodiments, an additional chemical moiety facilitates delivery to liver. In certain embodiments, a provided ds oligonucleotide can comprise one or more linkers and additional chemical moieties (e.g., targeting moieties), and / or can be chirally 20 controlled or not chirally controlled, and / or have a bases sequence and / or one or more modifications and / or formats as described herein. Various linkers, carbohydrate moieties and targeting moieties, including many known in the art, can be utilized in accordance with the present disclosure. In certain embodiments, a carbohydrate moiety is a targeting moiety. In certain embodiments, a targeting moiety is a 25 carbohydrate moiety. In certain embodiments, an additional chemical moiety is or comprises an asialoglycoprotein receptor (ASGPR) ligand. Without wishing to be bound by any particular theory, the present disclosure notes that ASGPR1 has also been reported to be expressed in the hippocampus region and / or cerebellum 30 Purkinje cell layer of the mouse. http: / / mouse.brain-map.org / experiment / show / 2048 Various other ASGPR ligands are known in the art and can be utilized in accordance with the present disclosure. In certain embodiments, an ASGPR ligand is a carbohydrate. In certain embodiments, an ASGPR ligand is GalNac or a derivative or an analog thereof. In certain embodiments, an ASGPR ligand is one described in Sanhueza et al. J. Am. Chem. Soc., 164 088290.0189 2017, 139 (9), pp 3528–3536. In certain embodiments, an ASGPR ligand is one described in Mamidyala et al. J. Am. Chem. Soc., 2012, 134, pp 1978−1981. In certain embodiments, an ASGPR ligand is one described in US 20160207953. In certain embodiments, an ASGPR ligand is a substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol derivative disclosed in, e.g., US 5 20160207953. In certain embodiments, an ASGPR ligand is one described in, e.g., US 20150329555. In certain embodiments, an ASGPR ligand is a substituted-6,8- dioxabicyclo[3.2.1]octane-2,3-diol derivative disclosed e.g., in US 20150329555. In certain embodiments, an ASGPR ligand is one described in US 8877917, US 20160376585, US 10086081, or US 8106022. ASGPR ligands described in these documents are incorporated 10 herein by reference. Those skilled in the art will appreciate that various technologies are known in the art, including those described in these documents, for assessing binding of a chemical moiety to ASGPR and can be utilized in accordance with the present disclosure. In certain embodiments, a provided ds oligonucleotide is conjugated to an ASGPR ligand. In certain embodiments, a provided ds oligonucleotide comprises an ASGPR ligand. In certain 15 embodiments, an additional chemical moiety comprises an ASGPR ligand , , , wherein each variable is independently as described in the present disclosure. In certain embodiments, R is −H. In certain embodiments, R’ is −C(O)R. 20 In certain embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety is or comprises . certain embodiments, an additional chemical moiety is or comprises . In certain 165 088290.0189 embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety is or comprises optionally substituted . In certain embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety is or comprises. In 5 certain embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety is or comprises . In certain embodiments, an additional chemical moiety comprises one or more moieties that can bind to, e.g., oligonucleotide target cells. For example, in certain embodiments, an 10 additional chemistry moiety comprises one or more protein ligand moieties, e.g., in certain embodiments, an additional chemical moiety comprises multiple moieties, each of which independently is an ASGPR ligand Certain additional chemical moieties (e.g., lipid moieties, targeting moieties, carbohydrate moieties) and various linkers for connecting additional chemical moieties to ds 15 oligonucleotide chains, are described in WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 022473, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO2019032612, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, and / or WO 2019 / 032612, the additional chemical moieties and linkers of each 20 of which are independently incorporated herein by reference, and can be utilized in accordance with the present disclosure. In certain embodiments, an additional chemical moiety is 166 088290.0189 digoxigenin or biotin or a derivative thereof. In certain embodiments, an additional chemical moiety is one described in WO 5 2012 / 030683. In certain embodiments, a provided ds oligonucleotide comprises a chemical structure (e.g., a linker, lipid, solubilizing group, and / or targeting ligand) described in WO 2012 / 030683. In certain embodiments, a provided ds oligonucleotide comprises an additional chemical moiety and / or a modification (e.g., of nucleobase, sugar, internucleotidic linkage, 10 etc.) described in: U.S. Pat. Nos. 5,688,941; 6,294,664; 6,320,017; 6,576,752; 5,258,506; 5,591,584; 4,958,013; 5,082,830; 5,118,802; 5,138,045; 6,783,931; 5,254,469; 5,414,077; 5,486,603; 5,112,963; 5,599,928; 6,900,297; 5,214,136; 5,109,124; 5,512,439; 4,667,025; 5,525,465; 5,514,785; 5,565,552; 5,541,313; 5,545,730; 4,835,263; 4,876,335; 5,578,717; 5,580,731; 5,451,463; 5,510,475; 4,904,582; 5,082,830; 4,762,779; 4,789,737; 4,824,941; 15 4,828,979; 5,595,726; 5,214,136; 5,245,022; 5,317,098; 5,371,241; 5,391,723; 4,948,882; 5,218,105; 5,112,963; 5,567,810; 5,574,142; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 5,585,481; 5,292,873; 5,552,538; 5,512,667; 5,597,696; 5,599,923; 7,037,646; 5,587,371; 5,416,203; 5,262,536; 5,272,250; or 8,106,022. In certain embodiments, an additional chemical moiety, e.g., a Mod, is connected via a 20 linker. Various linkers are available in the art and may be utilized in accordance with the present disclosure, for example, those utilized for conjugation of various moieties with proteins (e.g., with antibodies to form antibody-drug conjugates), nucleic acids, etc. Certain useful linkers are described in US 9982257, US 20170037399, US 20180216108, US 20180216107, US 9598458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 25 2017 / 210647, WO 2018 / 098264, WO 2018 / 223056, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, and / or WO 2019 / 032612, the linker moieties of each which are independently incorporated herein by reference 30 Metabolites and Shortened Versions of Oligonucleotides In some embodiments, a ds oligonucleotide targeting INHBE corresponds to a metabolite produced by cleavage (e.g., enzymatic cleavage by a nuclease) of a longer oligonucleotide, e.g., a longer ds oligonucleotide targeting INHBE. In some embodiments, the present disclosure pertains to a ds oligonucleotide targeting INHBE which corresponds to a 167 088290.0189 portion, or fragment of a ds oligonucleotide targeting INHBE disclosed herein. In some embodiments, the present disclosure pertains to an oligonucleotide which corresponds to a metabolite of a ds oligonucleotide targeting INHBE disclosed herein. In some embodiments, the present disclosure pertains to an oligonucleotide which is 1, 2, 3, 4, 5, 6, 7, 5 8, 9, 10, 11, 12, 13, or more bases shorter than an oligonucleotide disclosed herein. In some embodiments, the present disclosure pertains to an oligonucleotide which has a base sequence which is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more bases shorter than that of an oligonucleotide disclosed herein. In some embodiments, a metabolite is designated as 3’-N-#, or 5’-N-#, wherein the # 10 indicates the number of bases removed, and the 3’ or 5’ indicates which end of the molecule from which the bases were deleted. For example, 3’-N-1 indicates a fragment or metabolite wherein 1 base was removed from the 3’ end. In some embodiments, the present disclosure perhaps to an oligonucleotide which corresponds to a fragment or metabolite of an oligonucleotide disclosed herein, wherein the 15 fragment or metabolite can be described as corresponding to 3’-N-1, 3’-N-2, 3’-N-3, 3’-N-4, 3’-N-5, 3’-N-6, 3’-N-7, 3’-N-8, 3’-N-9, 3’-N-10, 3’-N-11, 3’-N-12, 5’-N-1, 5’-N-2, 5’-N-3, 5’- N-4, 5’-N-5, 5’-N-6, 5’-N-7, 5’-N-8, 5’-N-9, 5’-N-10, 5’-N-11, or 5’-N-12 of an oligonucleotide described herein, wherein each T may be independently replaced with U and vice versa. 20 In some embodiments, the present disclosure pertains to an oligonucleotide which corresponds to a metabolite of an oligonucleotide, wherein the metabolite is truncated on the 5’ and / or 3’ end relative to the oligonucleotide disclosed herein, wherein each T may be independently replaced with U and vice versa. In some embodiments, the present disclosure pertains to an which corresponds to a metabolite of an oligonucleotide, wherein the metabolite 25 is truncated on both the 5’ and 3’ end relative to the oligonucleotide disclosed herein, wherein each T may be independently replaced with U and vice versa. In some embodiments, the present disclosure pertains to an oligonucleotide which is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more total bases shorter on the 5’ and / or 3’ end than an oligonucleotide disclosed herein. In some embodiments, the present disclosure pertains to an oligonucleotide which has a base 30 sequence which is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more bases total shorter on the 5’ and / or 3’ end than that of an oligonucleotide disclosed herein, wherein each T may be independently replaced with U and vice versa. In some embodiments, the present disclosure pertains to an oligonucleotide which is a product of a cleavage of an oligonucleotide disclosed herein cleaved at a natural phosphate 168 088290.0189 linkage. In some embodiments, the present disclosure pertains to an oligonucleotide which is a product of a cleavage of an oligonucleotide disclosed herein cleaved at a Rp phosphorothioate internucleotidic linkage. Various technologies can be utilized to identify, characterize and / or assess metabolites 5 and / or shortened ds oligonucleotides targeting INHBE in accordance with the present disclosure, for example, those described in US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0249173, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2019 / 032607, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, WO 2019 / 032612, and / or WO 2020 / 191252. 10 Treatment of INHBE-Associated Conditions, disorders, or diseases In some embodiments, the present disclosure provides a ds oligonucleotide targeting INHBE, which targets INHBE and directs target-specific knockdown of INHBE. In some embodiments, the present disclosure provides methods for preventing and / or treating INHBE- 15 associated conditions, disorders, or diseases using provided ds oligonucleotides targeting INHBE and compositions thereof. In some embodiments, the present disclosure provides oligonucleotides and compositions thereof for use as medicaments, e.g., for INHBE-associated conditions, disorders, or diseases. In some embodiments, the present disclosure provides oligonucleotides and compositions thereof for use in the treatment of INHBE-associated 20 conditions, disorders, or diseases. In some embodiments, the present disclosure provides oligonucleotides and compositions thereof for the manufacture of medicaments for the treatment of INHBE-associated conditions, disorders, or diseases. In particular embodiments, the present disclosure provides dsRNAi agents for treating and / or ameliorating one or more symptoms associated with an INHBE-associated condition, disorder, or disease. 25 In some embodiments, the present disclosure provides a method for treating and / or ameliorating one or more symptoms associated with an INHBE-associated condition, disorder, or disease in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a ds oligonucleotide or dsRNAi agent targeting INHBE or a composition thereof. In some embodiments, the present disclosure provides a method for 30 reducing susceptibility to an INHBE-associated condition, disorder, or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a ds oligonucleotide or dsRNAi agent targeting INHBE or a composition thereof. In some embodiments, the present disclosure provides a method for preventing or delaying the onset of an INHBE-associated condition, disorder, or disease in a mammal in need thereof, the 169 088290.0189 method comprising: administering to the mammal a therapeutically effective amount of a ds oligonucleotide or dsRNAi agent targeting INHBE or a composition thereof. In some embodiments, the present disclosure provides a method for treating and / or ameliorating one or more symptoms associated with an INHBE-associated condition, disorder, or disease in a 5 mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a ds oligonucleotide or dsRNAi agent targeting INHBE. In some embodiments, the present disclosure provides a method for reducing susceptibility to an INHBE-associated condition, disorder, or disease in a mammal in need 10 thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a ds oligonucleotide or dsRNAi agent targeting INHBE. In some embodiments, the present disclosure provides a method for preventing or delaying the onset of an INHBE-associated condition, disorder, or disease in a mammal in need thereof, the method comprising: administering to the mammal a 15 therapeutically effective amount of a nucleic acid-lipid particle comprising a ds oligonucleotide or dsRNAi agent targeting INHBE. In some embodiments, a mammal is a human. In some embodiments, a mammal is susceptible to, afflicted with and / or suffering from an INHBE- associated condition, disorder, or disease. In some embodiments, the present disclosure provides the use of the dsRNAi agent for 20 reducing susceptibility to an INHBE-associated condition, disorder, or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a ds oligonucleotide or dsRNAi agent targeting INHBE. In some embodiments, the present disclosure provides the use of the dsRNAi agent for preventing or delaying the onset of an INHBE-associated condition, disorder, or 25 disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a ds oligonucleotide or dsRNAi agent targeting INHBE. In some embodiments, a mammal is a human. In some embodiments, a mammal is susceptible to, afflicted with and / or suffering from an INHBE- associated condition, disorder, or disease. In some embodiments, the present disclosure 30 provides the use of the dsRNAi agent for preventing or treating of an INHBE-related disorder in a subject in need thereof. In certain embodiments, the subject is a mammal. In particular embodiment, the subject is a human. In some embodiments, an INHBE-associated condition, disorder, or disease includes, but is not limited to, improving glucose control; increasing lean body mass; reducing fat mass; 170 088290.0189 a metabolic disorder; diabetes, e.g., type 2 diabetes; insulin resistance; obesity; elevated triglyceride level; lipodystrophy; liver inflammation; fatty liver disease; hypercholesterolemia; an elevated liver enzyme; nonalcoholic steatohepatitis (NASH); a cardiovascular disease; coronary artery disease; cardiomyopathy; high blood pressure; heart failure; chronic kidney 5 disease; and liver issues associated with increased fat mass, obesity, and / or diabetes. In alternative embodiments, the INHBE-related disorder is selected from: improving glucose control; increasing lean body mass; reducing fat mass; treating obesity, e.g., abdominal obesity; treating diabetes, e.g., type 2 diabetes; treating insulin resistance; coronary artery disease; treating chronic kidney disease; treating liver issues associated with increased fat mass, 10 obesity, and / or diabetes; treating a metabolic disorder; treating an elevated triglyceride level; treating a lipodystrophy; treating liver inflammation; treating fatty liver disease; treating hypercholesterolemia; treating an elevated liver enzyme; treating nonalcoholic steatohepatitis (NASH); treating a cardiovascular disease; treating cardiomyopathy; treating high blood pressure; treating heart failure; and inducing lipolysis (fat-burning) while preserving muscle 15 mass. A composition which comprises the dsRNAi agent, optionally with a second agent, can be administered to a subject, to treat or prevent an INHBE-related disorder. In certain embodiments, a composition comprising the dsRNAi agent is administered to a subject in need to treat or prevent an INHBE-related disorder. In alternative embodiments, a composition 20 comprising the dsRNAi agent and a second agent is administered to subject in need to treat an INHBE-related disorder. In particular embodiments the dsRNAi agent for use in preventing or treating an INHBE-related disorder is administered with a second agent. In certain embodiments, the dsRNAi agent for use in preventing or treating an INHBE-related disorder further comprises administering a second agent. 25 In particular embodiments, the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; 30 meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof. In certain embodiments, the second agent is a GLP-1 receptor agonist, where the GLP-1 agonist is selected from the group consisting of exenatide, 171 088290.0189 dulaglutide, liraglutide, tirzepatide, and semaglutide. In preferred embodiments, the GLP-1 agonist is semaglutide. The dsRNAi agent is administered daily, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, every 5 seven months, every eight months, every nine months, every ten months, every eleven months, or annually. In particular embodiments, the second agent is administered daily. In certain embodiments, the second agent is administered weekly. In particular embodiments, the dsRNAi agent is administered every six months. In particular embodiments, the dsRNAi agent is administered annually. 10 The second agent is administered daily, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or annually. In particular embodiments, the second agent is administered daily. In certain embodiments, the second agent is administered weekly. In particular embodiments, the second 15 agent is administered every six months. The dsRNAi agent and second agent can be administered to the subject sequentially or concurrently. In particular embodiments, the dsRNAi agent and second agent are administered sequentially. In certain embodiments, the dsRNAi agent and second agent are administered concurrently. When the dsRNAi agent and the second agent are administered concurrently, the 20 administration of the second agent continues upon said administration of the dsRNAi agent to the subject or the administration of the second agent terminates upon said administration of the dsRNAi agent to the subject. In particular embodiments, the administration of the second agent continues upon administration of the dsRNAi agent. In certain embodiments, the administration of the second agent terminates upon administration of the dsRNAi agent to the subject. 25 Additionally, the amount of the second agent administered is reduced from standard doses in the art when administered with a dsRNAi agent compared to when administered alone. The second agent, when administered alone, is provided to the subject in standard amounts known in the art. When the dsRNAi agent and the second agent are both administered to the subject, the dose of the second agent can be the same or reduced so that the second agent is 30 administered in an amount less than when the second agent is administered alone. In particular embodiments, the amount of the second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent. In certain embodiments, the subject is administered the second agent in a dosage amount that is the same as or lower than a standard dosage amount. In certain embodiments, the subject is 172 088290.0189 administered a GLP-1 agonist in a dosage amount that is the same as or lower than a standard dosage amount. In certain embodiments, the subject is administered the second agent in a dosage amount that is lower than a standard dosage amount. In certain embodiments, the subject is administered a GLP-1 agonist in a dosage amount that is lower than a standard dosage 5 amount The compositions or dsRNAi agents disclosed herein are additionally used in treatment of an INHBE-related disorder in combination with performing bariatric surgery, administering a second agent, or a combination performing bariatric surgery and administering a second agent. In certain embodiments, an INHBE-related is prevented or treated by administering to 10 the subject the dsRNAi agents and administering a second agent. In particular embodiments, an INHBE-related disorder is prevented or treated by administering to the subject the dsRNAi agents and performing bariatric surgery. In alternative embodiments, an INHBE-related disorder is prevented or treated by administering to the subject the dsRNAi agents, administering a second agent, and performing bariatric surgery. In certain embodiments the 15 dsRNAi agent is administered to the subject prior to, concurrently with, and / or after performing bariatric surgery and / or administering a second agent. In particular embodiments, dsRNAi agent is administered to the subject prior to, concurrently with, and / or after performing bariatric surgery and / or administering a second agent, wherein the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a 20 norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a 25 HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof. In certain embodiments, the second agent is a GLP-1 receptor agonist, where the GLP-1 agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, tirzepatide, and semaglutide. In preferred embodiments, the GLP-1 agonist is 30 semaglutide. After the subject has undergone bariatric surgery or been administered a second agent, the dsRNAi agent is administered daily, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, every seven months, 173 088290.0189 every eight months, every nine months, every ten months, every eleven months, or annually. In preferred embodiments, after the subject has undergone bariatric surgery or been administered a second agent, the dsRNAi agent is administered every six months. In alternative embodiments, after the subject has undergone bariatric surgery or been administered a second 5 agent, the dsRNAi agent is administered annually. The loss of body weight by the subject when administered the dsRNAi agent and the second agent is substantially more than when the subject is administered the second agent alone. In particular embodiments, the subject loses about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 125%, 150%, 175%, or 200% more 10 weight when administered the dsRNAi agent and the second than a subject administered the second agent alone. In certain embodiments, the subject loses about double, about triple, or about quadruple the body weight compared to when the subject is administered the second agent alone. In certain embodiments, the subject loses about double the body weight compared to when the subject is administered the second agent alone. In addition, when administered the 15 dsRNAi agent and the second agent, the subject does not undergo rebound body weight gain which is expected when the subject is administered the second agent alone. The dsRNAi agents of the present disclosure is administered daily, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, 20 every eleven months, or annually. In preferred embodiments, the dsRNAi agent is administered every six months. In alternative embodiments, the dsRNAi agent is administered annually. Administration of the dsRNAi agent to the subject is orally or parenterally. Parenteral administration includes administration intradermally, subcutaneously, intramuscularly, and intravenously. In particular embodiments, the dsRNAi agent is administered subcutaneously. 25 When administered the dsRNAi agent or compositions provided herein, the subject maintains at least 50%, 60%, 75%, 90%, or 95% of its pre-administration skeletal muscle mass. In particular embodiments, the subject loses body weight without any loss or without substantial loss of muscle mass. In certain embodiments, the subject loses body weight without any loss of muscle mass. In particular embodiments, the subject loses body weight without 30 substantial loss of muscle mass. The loss of body weight the subject is administered the dsRNAi agent or compositions provided herein is accompanied a reduction in fat mass. In particular embodiments, the fat mass is visceral fat mass. The effects on the subject’s muscle mass and fat mass are consistent with the protective effects of heterozygous INHBE loss-of-function (LoF) mutations. 174 088290.0189 Additionally, when administered the dsRNAi agent or compositions provided herein the subject maintains a healthy metabolic profile. In particular embodiments, the infiltration of activated macrophages in visceral adipose is decreased by at least about 10%, 20%, 30%4, 40%, 50%, 60%, 70%, 90%, or 90%. In particular embodiments, the infiltration of activated 5 macrophages in visceral adipose is decreased by at least about 50%. The decrease in infiltration of activation macrophages in viseceral adipose is associated with treating type 2 diabetes and / or coronary artery disease. In particular embodiments, type 2 diabetes and / or coronary artery disease is secondary to obesity. 10 Administration of Oligonucleotides and Compositions Many delivery methods, regimen, etc. can be utilized in accordance with the present disclosure for administering provided ds oligonucleotides and compositions thereof (typically pharmaceutical compositions for therapeutic purposes), including various technologies known in the art. 15 In some embodiments, an oligonucleotide composition, e.g., a ds oligonucleotide targeting INHBE composition, is administered at a dose and / or frequency lower than that of an otherwise comparable reference oligonucleotide composition and has comparable or improved effects. In some embodiments, a chirally controlled oligonucleotide composition is administered at a dose and / or frequency lower than that of a comparable, otherwise identical 20 stereorandom reference oligonucleotide composition and with comparable or improved effects, e.g., in improving the knockdown of the target transcript. In some embodiments, the present disclosure recognizes that properties and activities, e.g., knockdown activity, stability, toxicity, etc. of oligonucleotides and compositions thereof can be modulated and optimized by chemical modifications and / or stereochemistry. In some 25 embodiments, the present disclosure provides methods for optimizing oligonucleotide properties and / or activities through chemical modifications and / or stereochemistry. In some embodiments, the present disclosure provides oligonucleotides and compositions thereof with improved properties and / or activities. Without wishing to be bound by any theory, due to, e.g., their better activity, stability, delivery, distribution, toxicity, pharmacokinetic, 30 pharmacodynamics and / or efficacy profiles, Applicant notes that provided oligonucleotides and compositions thereof in some embodiments can be administered at lower dosage and / or reduced frequency to achieve comparable or better efficacy, and in some embodiments can be administered at higher dosage and / or increased frequency to provide enhanced effects. In some embodiments, the present disclosure provides, in a method of administering an 175 088290.0189 oligonucleotide composition comprising a plurality of oligonucleotides sharing a common base sequence, the improvement comprising administering an oligonucleotide comprising a plurality of oligonucleotides that is characterized by improved delivery relative to a reference oligonucleotide composition of the same common base sequence. 5 In some embodiments, provided oligonucleotides, compositions and methods provide improved delivery. In some embodiments, provided oligonucleotides, compositions and methods provide improved cytoplasmatic delivery. In some embodiments, improved delivery is to a population of cells. In some embodiments, improved delivery is to a tissue. In some embodiments, improved delivery is to an organ. In some embodiments, improved delivery is 10 to an organism, e.g., a patient or subject. Example structural elements (e.g., chemical modifications, stereochemistry, combinations thereof, etc.), oligonucleotides, compositions and methods that provide improved delivery are extensively described in the present disclosure. Various dosing regimens can be utilized to administer oligonucleotides and compositions of the present disclosure. In some embodiments, multiple unit doses are 15 administered, separated by periods of time. In some embodiments, a given composition has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some 20 embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one 25 or more additional doses in a second (or subsequent) dose amount that is the same as or different from the first dose (or another prior dose) amount. In some embodiments, a chirally controlled oligonucleotide composition is administered according to a dosing regimen that differs from that utilized for a non-chirally controlled (e.g., stereorandom) oligonucleotide composition of the same sequence, and / or of a different chirally controlled oligonucleotide 30 composition of the same sequence. In some embodiments, a chirally controlled oligonucleotide composition is administered according to a dosing regimen that is reduced as compared with that of a chirally uncontrolled (e.g., stereorandom) oligonucleotide composition of the same sequence in that it achieves a lower level of total exposure over a given unit of time, involves one or more lower unit doses, and / or includes a smaller number of doses over a given unit of 176 088290.0189 time. In some embodiments, a chirally uncontrolled oligonucleotide is administered according to a dosing regimen that extends for a longer period of time than does that of a chirally uncontrolled (e.g., stereorandom) oligonucleotide composition of the same sequence Without wishing to be limited by theory, Applicant notes that in some embodiments, the shorter dosing 5 regimen, and / or longer time periods between doses, may be due to the improved stability, bioavailability, and / or efficacy of a chirally controlled oligonucleotide composition. In some embodiments, with their improved delivery (and other properties), provided compositions can be administered in lower dosages and / or with lower frequency to achieve biological effects, for example, clinical efficacy. 10 The dsRNAi agents of the present disclosure is administered to a subject daily, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or annually. In preferred embodiments, the dsRNAi agent is administered every six months. In alternative embodiments, the dsRNAi agent is administered 15 annually. The dsRNAi agent is administered orally or parenterally. Parenteral administration includes administration intradermally, subcutaneously, intramuscularly, and intravenously. In particular embodiments, the dsRNAi agent is administered subcutaneously. When the dsRNAi agent and the second agent, as defined herein, are administered to a subject, the dose of the second agent can be the same or reduced so that the second agent is 20 administered in an amount less than when the second agent is administered alone. In particular embodiments, the amount of the second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent. In certain embodiments, the subject is administered the second agent in a dosage amount that is the same as or lower than a standard dosage amount. In certain embodiments, the subject is 25 administered a GLP-1 agonist in a dosage amount that is the same as or lower than a standard dosage amount. In certain embodiments, the subject is administered the second agent in a dosage amount that is lower than a standard dosage amount. In certain embodiments, the subject is administered a GLP-1 agonist in a dosage amount that is lower than a standard dosage amount 30 Pharmaceutical Compositions When used as therapeutics, a provided ds oligonucleotide, e.g., a ds oligonucleotide targeting INHBE, or oligonucleotide composition thereof is typically administered as a pharmaceutical composition. In some embodiments, the present disclosure provides 177 088290.0189 pharmaceutical compositions comprising a provided compound, e.g., an oligonucleotide, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. In some embodiments, for therapeutic and clinical purposes, oligonucleotides of the present disclosure are provided as pharmaceutical compositions. As appreciated by those skilled in the art, oligonucleotides 5 of the present disclosure can be provided in their acid, base or salt forms. In some embodiments, oligonucleotides can be in acid forms, e.g., for natural phosphate linkages, in the form of −OP(O)(OH)O−; for phosphorothioate internucleotidic linkages, in the form of −OP(O)(SH)O−; etc. In some embodiments, ds oligonucleotides targeting INHBE can be in salt forms, e.g., for natural phosphate linkages, in the form of −OP(O)(ONa)O− in sodium salts; 10 for phosphorothioate internucleotidic linkages, in the form of −OP(O)(SNa)O− in sodium salts; etc. Unless otherwise noted, oligonucleotides of the present disclosure can exist in acid, base and / or salt forms. In some embodiments, a pharmaceutical composition is a liquid composition. In some embodiments, a pharmaceutical composition is provided by dissolving a solid oligonucleotide 15 composition, or diluting a concentrated oligonucleotide composition, using a suitable solvent, e.g., water or a pharmaceutically acceptable buffer. In some embodiments, liquid compositions comprise anionic forms of provided oligonucleotides and one or more cations. In some embodiments, liquid compositions have pH values in the weak acidic, about neutral, or basic range. In some embodiments, pH of a liquid composition is about a physiological pH, e.g., 20 about 7.4. In some embodiments, a provided oligonucleotide is formulated for administration to and / or contact with a body cell and / or tissue expressing its target. For example, in some embodiments, a provided ds oligonucleotide targeting INHBE is formulated for administration to a body cell and / or tissue expressing INHBE. In some embodiments, such a body cell and / or 25 tissue are a neuron or a cell and / or tissue of the central nervous system. In some embodiments, broad distribution of oligonucleotides and compositions may be achieved with intraparenchymal administration, intrathecal administration, or intracerebroventricular administration. In some embodiments, the pharmaceutical composition is formulated for intravenous 30 injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration. In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop. 178 088290.0189 In some embodiments, the present disclosure provides a pharmaceutical composition comprising chirally controlled oligonucleotide or composition thereof, in admixture with a pharmaceutically acceptable inactive ingredient (e.g., a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, etc.). In some embodiments, the present disclosure 5 provides a pharmaceutical composition delivering chirally controlled oligonucleotide or composition thereof, in admixture with a pharmaceutically acceptable inactive ingredient (e.g., a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, etc.). One of skill in the art will recognize that the pharmaceutical compositions include pharmaceutically acceptable salts of provided oligonucleotide or compositions. In some embodiments, a 10 pharmaceutical composition is a chirally controlled oligonucleotide composition. In some embodiments, a pharmaceutical composition is a stereopure oligonucleotide composition. In some embodiments, the present disclosure provides salts of oligonucleotides and pharmaceutical compositions thereof. In some embodiments, a salt is a pharmaceutically acceptable salt. In some embodiments, a pharmaceutical composition comprises an 15 oligonucleotide, optionally in its salt form, and a sodium salt. In some embodiments, a pharmaceutical composition comprises an oligonucleotide, optionally in its salt form, and sodium chloride. In some embodiments, each hydrogen ion of an oligonucleotide that may be donated to a base (e.g., under conditions of an aqueous solution, a pharmaceutical composition, etc.) is replaced by a non-H+cation. For example, in some embodiments, a pharmaceutically 20 acceptable salt of an oligonucleotide is an all-metal ion salt, wherein each hydrogen ion (for example, of −OH, −SH, etc.) of each internucleotidic linkage (e.g., a natural phosphate linkage, a phosphorothioate internucleotidic linkage, etc.) is replaced by a metal ion. Various suitable metal salts for pharmaceutical compositions are widely known in the art and can be utilized in accordance with the present disclosure. In some embodiments, a pharmaceutically acceptable 25 salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is magnesium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is an ammonium salt (cation N(R)4+). In some embodiments, a pharmaceutically acceptable salt comprises one and no more than one types of cation. In 30 some embodiments, a pharmaceutically acceptable salt comprises two or more types of cation. In some embodiments, a cation is Li+, Na+, K+, Mg2+or Ca2+. In some embodiments, a pharmaceutically acceptable salt is an all-sodium salt. In some embodiments, a pharmaceutically acceptable salt is an all-sodium salt, wherein each internucleotidic linkage which is a natural phosphate linkage (acid form −O−P(O)(OH)−O−), if any, exists as its sodium 179 088290.0189 salt form (−O−P(O)(ONa)−O−), and each internucleotidic linkage which is a phosphorothioate internucleotidic linkage (acid form −O−P(O)(SH)−O−), if any, exists as its sodium salt form (−O−P(O)(SNa)−O−). Various technologies for delivering nucleic acids and / or oligonucleotides are known in 5 the art can be utilized in accordance with the present disclosure. For example, a variety of supramolecular nanocarriers can be used to deliver nucleic acids. Example nanocarriers include, but are not limited to liposomes, cationic polymer complexes and various polymeric compounds. Complexation of nucleic acids with various polycations is another approach for intracellular delivery; this includes use of PEGylated polycations, polyethyleneamine (PEI) 10 complexes, cationic block co-polymers, and dendrimers. Several cationic nanocarriers, including PEI and polyamidoamine dendrimers help to release contents from endosomes. Other approaches include use of polymeric nanoparticles, microspheres, liposomes, dendrimers, biodegradable polymers, conjugates, prodrugs, inorganic colloids such as sulfur or iron, antibodies, implants, biodegradable implants, biodegradable microspheres, osmotically 15 controlled implants, lipid nanoparticles, emulsions, oily solutions, aqueous solutions, biodegradable polymers, poly(lactide-coglycolic acid), poly(lactic acid), liquid depot, polymer micelles, quantum dots and lipoplexes. In some embodiments, an oligonucleotide is conjugated to another molecule. In therapeutic and / or diagnostic applications, compounds, e.g., oligonucleotides, of the 20 disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington, The Science and Practice of Pharmacy (20th ed. 2000). Pharmaceutically acceptable salts for basic moieties are generally well known to those of ordinary skill in the art, and may include, e.g., acetate, benzenesulfonate, besylate, benzoate, 25 bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, 30 salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington, The Science and Practice of Pharmacy (20th ed. 2000). Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, 180 088290.0189 succinate, sulfate, or tartrate. In some embodiments, ds oligonucleotides targeting INHBE are formulated in pharmaceutical compositions described in WO 2005 / 060697, WO 2011 / 076807 or WO 2014 / 136086. 5 Depending on the specific conditions, disorders, or diseases being treated, provided agents, e.g., oligonucleotides, may be formulated into liquid or solid dosage forms and administered systemically or locally. Provided oligonucleotides may be delivered, for example, in a timed- or sustained- low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington, The Science and 10 Practice of Pharmacy (20th ed. 2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra-sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or 15 another mode of delivery. For injection, provided agents, e.g., oligonucleotides may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulations. Such 20 penetrants are generally known in the art and can be utilized in accordance with the present disclosure. Use of pharmaceutically acceptable carriers to formulate compounds, e.g., provided oligonucleotides, for the practice of the disclosure into dosages suitable for various mods of administration is well known in the art. With proper choice of carrier and suitable 25 manufacturing practice, compositions of the present disclosure, e.g., those formulated as solutions, may be administered via various routes, e.g., parenterally, such as by intravenous injection. In some embodiments, a composition comprising a ds oligonucleotide targeting INHBE further comprises any or all of: calcium chloride dihydrate, magnesium chloride hexahydrate, 30 potassium chloride, sodium chloride, sodium phosphate dibasic anhydrous, sodium phosphate, monobasic dihydrate, and / or water for Injection. In some embodiments, a composition further comprises any or all of: calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.77 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic 181 088290.0189 dihydrate (0.05 m g) USP, and Water for Injection USP. In some embodiments, a composition comprising an oligonucleotide further comprises any or all of: cholesterol, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4- (dimethylamino) butanoate(DLin-MC3-DMA), 1,2-distearoyl-sn-glycero-3-phosphocholine 5 (DSPC), alpha-(3’-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-omega-methoxy, polyoxyethylene(PEG2000-C-DMG), potassium phosphate monobasic anhydrous NF, sodium chloride, sodium phosphate dibasic heptahydrate, and Water for Injection. In some embodiments, the pH of a composition comprising a ds oligonucleotide targeting INHBE is ~7.0. In some embodiments, a composition comprising an oligonucleotide further comprises10 any or all of: 6.2 mg cholesterol USP, 13.0 mg (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31- tetraen-19-yl-4-(dimethylamino) butanoate(DLin-MC3-DMA), 3.3 mg 1,2-distearoyl-sn- glycero-3-phosphocholine (DSPC), 1.6 mg α-(3’-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene(PEG2000-C-DMG), 0.2 mg potassium phosphate monobasic anhydrous NF, 8.8 mg sodium chloride USP, 2.3 mg sodium phosphate 15 dibasic heptahydrate USP, and Water for Injection USP, in an approximately 1 mL total volume. Provided compounds, e.g., oligonucleotides, can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. In some embodiments, such carriers enable provided oligonucleotides to be 20 formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for, e.g., oral ingestion by a subject (e.g., patient) to be treated. For nasal or inhalation delivery, provided compounds, e.g., oligonucleotides, may be formulated by methods known to those of skill in the art, and may include, e.g., examples of solubilizing, diluting, or dispersing substances such as saline, preservatives, such as benzyl 25 alcohol, absorption promoters, and fluorocarbons. In certain embodiments, parenteral administration is by injection, by, e.g., a syringe, a pump, etc. In certain embodiments, an injection is a bolus injection. In certain embodiments, an injection is administered directly to a tissue or location, such as striatum, caudate, cortex, hippocampus and / or cerebellum. 30 In certain embodiments, methods of specifically localizing provided compounds, e.g., oligonucleotides, such as by bolus injection, may decrease median effective concentration (EC50) by a factor of 20, 25, 30, 35, 40, 45 or 50. In certain embodiments, a targeted tissue is brain tissue. In certain embodiments, a targeted tissue is striatal tissue. In certain embodiments, decreasing EC50 is desirable because it reduces the dose required to achieve a pharmacological 182 088290.0189 result in a patient in need thereof. In certain embodiments, a provided oligonucleotide is delivered by injection or infusion once every week, every two weeks, every month, every two months, every 90 days, every 3 months, every 6 months, twice a year or once a year. 5 Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients, e.g., oligonucleotides, are contained in effective amounts to achieve their intended purposes. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. 10 In addition to active ingredients, pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of an active compound into preparations which can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions. 15 In some embodiments, pharmaceutical compositions for oral use can be obtained by combining an active compound with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat 20 starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. 25 In some embodiments, dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different 30 combinations of active compound doses. Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients, e.g., oligonucleotides, in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or 183 088290.0189 magnesium stearate and, optionally, stabilizers. In soft capsules, active compounds, e.g., oligonucleotides, may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added. In some embodiments, a provided composition comprises a lipid. In some 5 embodiments, a lipid is conjugated to an active compound, e.g., an oligonucleotide. In some embodiments, a lipid is not conjugated to an active compound. In some embodiments, a lipid comprises a C10-C40linear, saturated or partially unsaturated, aliphatic chain. In some embodiments, a lipid comprises a C10-C40 linear, saturated or partially unsaturated, aliphatic chain, optionally substituted with one or more C1-4 aliphatic group. In some embodiments, the 10 lipid is selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, docosahexaenoic acid (cis-DHA), turbinaric acid and dilinoleyl alcohol. In some embodiments, an active compound is a provided oligonucleotide. In some embodiments, a composition comprises a lipid and an active compound, and further comprises another component which is another lipid 15 or a targeting compound or moiety. In some embodiments, a lipid is an amino lipid; an amphipathic lipid; an anionic lipid; an apolipoprotein; a cationic lipid; a low molecular weight cationic lipid; a cationic lipid such as CLinDMA and DLinDMA; an ionizable cationic lipid; a cloaking component; a helper lipid; a lipopeptide; a neutral lipid; a neutral zwitterionic lipid; a hydrophobic small molecule; a hydrophobic vitamin; a PEG-lipid; an uncharged lipid modified20 with one or more hydrophilic polymers; phospholipid; a phospholipid such as 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine; a stealth lipid; a sterol; a cholesterol; a targeting lipid; or another lipid described herein or reported in the art suitable for pharmaceutical uses. In some embodiments, a composition comprises a lipid and a portion of another lipid capable of mediating at least one function of another lipid. In some embodiments, a targeting compound 25 or moiety is capable of targeting a compound (e.g., an oligonucleotide) to a particular cell or tissue or subset of cells or tissues. In some embodiments, a targeting moiety is designed to take advantage of cell- or tissue-specific expression of particular targets, receptors, proteins, or another subcellular component. In some embodiments, a targeting moiety is a ligand (e.g., a small molecule, antibody, peptide, protein, carbohydrate, aptamer, etc.) that targets a 30 composition to a cell or tissue, and / or binds to a target, receptor, protein, or another subcellular component. Certain example lipids for delivery of an active compound, e.g., an oligonucleotide, allow (e.g., do not prevent or interfere with) the function of an active compound. In some embodiments, a lipid is lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic 184 088290.0189 acid, alpha-linolenic acid, gamma-linolenic acid, docosahexaenoic acid (cis-DHA), turbinaric acid or dilinoleyl alcohol. As described in the present disclosure, lipid conjugation, such as conjugation with fatty acids, may improve one or more properties of oligonucleotides. 5 In some embodiments, a composition for delivery of an active compound, e.g., an oligonucleotide, is capable of targeting an active compound to particular cells or tissues as desired. In some embodiments, a composition for delivery of an active compound is capable of targeting an active compound to a muscle cell or tissue. In some embodiments, the present disclosure provides compositions and methods related to delivery of active compounds, 10 wherein the compositions comprise an active compound and a lipid. In various embodiments to a muscle cell or tissue, a lipid is selected from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, docosahexaenoic acid (cis-DHA), turbinaric acid and dilinoleyl alcohol. In some embodiments, a ds oligonucleotide targeting INHBE is delivered via a 15 composition comprising any one or more of, or a method of delivery involving the use of any one or more of: transferrin receptor-targeted nanoparticle; cationic liposome-based delivery strategy; cationic liposome; polymeric nanoparticle; viral carrier; retrovirus; adeno-associated virus; stable nucleic acid lipid particle; polymer; cell-penetrating peptide; lipid; dendrimer; neutral lipid; cholesterol; lipid-like molecule; fusogenic lipid; hydrophilic molecule;20 polyethylene glycol (PEG) or a derivative thereof; shielding lipid; PEGylated lipid; PEG-C- DMSO; PEG-C-DMSA; DSPC; ionizable lipid; a guanidinium-based cholesterol derivative; ion-coated nanoparticle; metal-ion coated nanoparticle; manganese ion-coated nanoparticle; angubindin-1; nanogel; incorporation of the INHBE targeting ds oligonucleotide into a branched nucleic acid structure; and / or incorporation of the INHBE targeting ds 25 oligonucleotide into a branched nucleic acid structure comprising 2, 3, 4 or more oligonucleotides. In some embodiments, a composition comprising an oligonucleotide is lyophilized. In some embodiments, a composition comprising an oligonucleotide is lyophilized, and the lyophilized oligonucleotide is in a vial. In some embodiments, the vial is back filled with 30 nitrogen. In some embodiments, the lyophilized oligonucleotide composition is reconstituted prior to administration. In some embodiments, the lyophilized oligonucleotide composition is reconstituted with a sodium chloride solution prior to administration. In some embodiments, the lyophilized oligonucleotide composition is reconstituted with a 0.9% sodium chloride solution prior to administration. In some embodiments, reconstitution occurs at the clinical site 185 088290.0189 for administration. In some embodiments, in a lyophilized composition, an oligonucleotide composition is chirally controlled or comprises at least one chirally controlled internucleotidic linkage and / or the ds oligonucleotide targets INHBE. Other features of certain embodiments will become apparent in the course of the 5 following descriptions of exemplary embodiments, which are given for illustration and are not intended to be limiting thereof. EXEMPLIFICATION Certain examples of provided technologies (compounds (oligonucleotides, reagents, 10 etc.), compositions, methods (methods of preparation, use, assessment, etc.), are described below. EXAMPLE 1. Oligonucleotide Synthesis Various technologies for preparing oligonucleotides and oligonucleotide compositions 15 (both stereorandom and chirally controlled) can be utilized in accordance with the present disclosure, including, for example, methods and reagents described in U.S. 9,394,333, U.S. 9,744,183, U.S. 9,605,019, U.S.9,598,458, U.S.9,982,257, U.S.10,160,969, U.S.10,479,995, U.S. 2020 / 0056173, U.S. 2018 / 0216107, U.S. 2019 / 0127733, U.S. 10,450,568, U.S. 2019 / 0077817, U.S. 2019 / 0249173, U.S. 2019 / 0375774, U.S. 2017 / 0037399, U.S. 20 2018 / 0216108, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, WO 2019 / 032612, WO 2020 / 191252, WO 2021 / 071858, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2022 / 099159, WO2023 / 201095, and WO 2024 / 182749. The methods and 25 reagents of each of which are incorporated herein by reference. Stereorandom and chirally controlled guide strand sequences were prepared utilizing the synthetic procedures as exemplified in above mentioned disclosures. Respective passenger strands were designed to have covalently linked GalNAc moiety as delivery vehicle at either end of sequences. Oligonucleotides with 5’-GalNAc modifications were synthesized by coupling C6-amino 30 modifier linker at the 5’-end of sequence. Oligonucleotides with 3’-GalNAc moiety as delivery vehicle were synthesized by utilizing 3’-C6 amino modified support. The single strand was cleaved from CPG by using deprotection condition as exemplified in earlier disclosures. The resulting amino group containing crude oligonucleotide was purified by ion exchange 186 088290.0189 chromatography on AKTA pure system using a sodium chloride gradient. Desired product was desalted and further used for conjugation with GalNAc acid. After conjugation reaction was found to be complete the material was further purified by ion exchange chromatography and desalted to achieve desired material. For introduction of PN linkages in guide and passenger 5 strands, specific PN coupling cycles were introduced at desired positions in oligonucleotide sequence utilizing the conditions as exemplified in WO2019 / 200185. In certain embodiments, oligonucleotides were prepared using suitable chiral auxiliaries, e.g., DPSE and PSM chiral auxiliaries. Various oligonucleotides, e.g., those in Table 1, and compositions thereof, were prepared in accordance with the present disclosure. 10 Various technologies can be utilized to assess properties and / or activities of provided oligonucleotides and compositions thereof. Some such technologies are described in this Example. Those skilled in the art appreciate that many other technologies can be readily utilized. As demonstrated herein, provided oligonucleotides and compositions, among other things, can be highly active, e.g., in reducing levels of their target nucleic acids. 15 Abbreviation 1X reagent: TEA-3HF : TEA : H2O : DMSO = 5.0 : 1.8 : 15.5 : 77.7 (v / v / v / v) ACN: acetonitrile ADIH: 2-azido-1,3-dimethylimidazolium hexafluorophosphate CMIMT: N-cyanomethylimidazolium triflate 20 CPG: controlled pore glass DCM: dichloromethane, CH2Cl2DIPEA: diisopropylethylamine DMSO: dimethylsulfoxide DMTr: 4,4′-dimethoxytrityl 25 GalNAc: N-acetylgalactosamine HF: hydrogen fluoride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate IBN: isobutyronitrile 30 MeCN: acetonitrile MeIm: N-methylimidazole PC: propylene carbonate TCA: trichloroacetic acid 187 088290.0189 TEA: triethylamine THF: tetrahydrofuran XH: xanthane hydride 5 General procedure for the synthesis of chiral-oligos (25 ^mol scale): The automated solid-phase synthesis of chiral-oligos was performed according to the cycles shown in Table 2 (regular amidite cycle, for PO linkages), Table 3 (regular amidite cycle, for stereo-random PS linkages), Table 4 (DPSE amidite cycle, for chiral PS linkages), and Table 5 (PSM amidite cycle, for chiral PN linkages). 10 Table 2. Regular Amidite Synthetic Cycle for PO linkages step operation reagents and solvent volume waiting time 1 detritylation 3% TCA / DCM 10 mL 65 s 02M m n m r / 20% IBN M CN 05 mL Table 3. Regular Amidite Synthetic Cycle for stereo-random PS linkages step operation reagents and solvent volume waiting time 1 detritylation 3% TCA / DCM 10 mL 65 s 02M m n m r / 20% IBN M CN 05 mL 15 Table 4. DPSE Amidite Synthetic Cycle for chiral PS linkages step operation reagents and solvent volume 1 detritylation 3% TCA / DCM 10 mL 65 s 188 088290.0189 2 coupling 0.2M monomer / 20% IBN-MeCN 0.5 mL 0.5M CMIMT / MeCN 1.0 mL 8 min 3 cap-1 20% Ac2O, 30% 2,6-lutidine / MeCN 2.0 mL 2 min 4 sulfurization 0.2M XH / pyridine 2.0 mL 6 min 5 cap-2 20% Ac2O, 30% 2,6-lutidine / 1.0 mL MeCN 20% MeIm / MeCN 1.0 mL Table 5. PSM Amidite Synthetic Cycle for chiral PN linkages step operation reagents and solvent volume waiting time 1 detritylation 3% TCA / DCM 10 mL 65 s 2 coupling 0.2M monomer / 20% IBN-MeCN 0.5 mL 0.5M CMIMT / MeCN 1.0 mL 8 min 3 cap-1 20% Ac2O, 30% 2,6-lutidine / MeCN . 2 min 4 imidation 0.5M ADIH reagent / MeCN 2.0 mL 6 min 5 cap-2 20% Ac2O, 30% 2,6-lutidine / 1.0 mL MeCN 20% MeIm / MeCN 1.0 mL General procedure for the C&D conditions (25 ^mol scale): 5 After completion of the synthesis, the CPG solid support was dried and transferred into 50 mL plastic tube. The CPG was treated with 1X reagent (2.5 mL; 100 ^L / umol) for 3 h at 28°C, then added conc. NH3(5.0 mL; 200 ^L / umol) for 24 h at 37°C. The reaction mixture was cooled to room temperature and the CPG was separated by membrane filtration, washed with 15 mL of H2O. The crude material (filtrate) was analyzed by LTQ and RP-UPLC. 10 General procedure for the purification conditions: The crude sense and antisense strands were purified separately by AEX chromatography. The purification run was performed using sodium hydroxide eluents. A sodium chloride gradient was used to elute the oligonucleotide from the column. The elution 15 profile was monitored by UV spectrophotometry, and the selected fraction pool (sense or antisense strand) was then concentrated and diafiltered against purified water to remove the purification buffer by TFF. The UF / DF process proceeded as follows, the selected pool of fractions was neutralized with sodium phosphate monobasic solution and then concentrated to 189 088290.0189 a target concentration. The concentrated oligonucleotide was diafiltered against purified water before final concentration to the target concentration and collected. General procedure for the annealing to form duplex: 5 The duplex was formed by combining equal molar quantities of the sense and antisense strands with mixing in an appropriately sized vessel. The formation of the duplex was confirmed by UPLC that there was no excess of single strands. The duplex oligonucleotide solution was filtered through a 0.2-micron filter and then placed in freeze drying tray for lyophilization. After lyophilization, the duplex was isolated as a white to off-white solid 10 powder. General procedure for the GalNAc conjugation conditions (1 ^mol scale): Into a plastic tube, tri-GalNAc (2.0 eq.), HATU (1.9 eq.), and DIPEA (10 eq.) were dissolved in anhydrous MeCN (0.5 mL). The mixture was stirred for 10 min at room 15 temperature, then the mixture was added into the amino-oligo (1 ^mol) in H2O (1 mL) and stirred for 1 h at 37 °C. The reaction was monitored by LC-MS and RP-UPLC. After the reaction was completed, the resultant GalNAc-conjugated oligo was treated with conc. NH3 (2 mL) for 1 h at 37 °C. The solution was concentrated under vacuum to remove MeCN and conc. NH3. The residue was then dissolved in H2O (10 mL) for reversed phase purification. 20 In addition, or alternatively to, the methods described above, the synthesis and deprotection of stereopure oligonucleotide sequences containing 5’-phosphonate can be performed as follows. Abbreviation: 25 ETT: 5-(Ethylthio)-1H-tetrazole CMIMT: N-cyanomethylimidazolium triflate ADIH: 2-azido-1,3-dimethylimidazolium hexafluorophosphate CPG: controlled pore glass DCM: dichloromethane, CH2Cl2 30 ACN: acetonitrile IBN: isobutyronitrile DMSO: Dimethyl sulfoxide MeIm: N-methylimidazole TCA: trichloroacetic acid 190 088290.0189 TEA: triethylamine TEA-3HF: triethylamine trihydrofluoride DS1 reagent: TEA-3HF : TEA : H2O : DMSO = 5.0 : 7.0 : 14.7 : 73.3 (v / v / v / v) TMSI: Trimethylsilyl iodide 5 XH: xanthane hydride Ac2O: acetic anhydride Vped5m: 5-(E)-vinylphosphonate-5-deoxy-5methyl General procedure for the synthesis of chiral-oligos (25 ^mol scale): 10 The automated solid-phase synthesis of chiral-oligos was performed according to the cycles shown in Table 6 (regular amidite cycle, for PO linkages), Table 7 (DPSE amidite cycle using 2’-deoxy-5’-phosphonate nucleosides, for chiral PS linkages), Table 8 (PSM amidite cycle using 2’-O-methyl and 2’-O-methoxyethyl nucleosides, for chiral PS linkages), Table 9 (PSM amidite cycle, for chiral PN linkages). All the amidites were dissolved into the 15 appropriate solvents (Acetonitrile or 20% isobutyronitrile in 80% acetonitrile), dried at least for 2 h under 4Å molecular sieves and then was used in the synthetic cycle. After the last coupling of 5’-phosponate amidite, the column was washed with 20% DEA in acetonitrile. Table 6. Regular Amidite Synthetic Cycle for PO linkages waiting step operation reagents and solvent volume time 1 detritylation 3% TCA / DCM 10 mL 65 s 0.2M monomer / 20% IBN- 0.5 mL 2 coupling MeCN 0.5M 8 min 1.0 mL ETT / MeCN 50mM I2 / pyridine-H2O (9:1, 3 oxidation 2.0 mL 1 min v / v) 20% Ac2O, 30% 2,6-lutidine / 1.0 mL 4 cap-2 45 s MeCN 20% MeIm / MeCN 1.0 mL 20 Table 7. DPSE Amidite Synthetic Cycle for chiral PS linkages 191 088290.0189 waiting step operation reagents and solvent volume time 1 detritylation 3% TCA / DCM 10 mL 65 s 0.2M monomer / 20% IBN- 0.5 mL 2 coupling MeCN 0.5M 8 min 1.0 mL CMIMT / MeCN 20% Ac2O, 30% 2,6-lutidine / 3 cap-1 2.0 mL 2 min MeCN 4 sulfurization 0.2M XH / pyridine 2.0 mL 6 min 20% Ac2O, 30% 2,6-lutidine / 1.0 mL 5 cap-2 45 s MeCN 20% MeIm / MeCN 1.0 mL Table 8. PSM Amidite Synthetic Cycle for chiral PS linkages waiting step operation reagents and solvent volume time 1 detritylation 3% TCA / DCM 10 mL 65 s 0.2M monomer / 20% IBN- 0.5 mL 2 coupling MeCN 0.5M 8 min 1.0 mL CMIMT / MeCN 20% Ac2O, 30% 2,6-lutidine / 3 cap-1 2.0 mL 2 min MeCN 4 sulfurization 0.2M XH / pyridine 2.0 mL 6 min 20% Ac2O, 30% 2,6-lutidine / 1.0 mL 5 cap-2 45 s MeCN 20% MeIm / MeCN 1.0 mL 5 Table 9. PSM Amidite Synthetic Cycle for chiral PN linkages (n001) waiting step operation reagents and solvent volume time 1 detritylation 3% TCA / DCM 10 mL 65 s 192 088290.0189 0.2M monomer / 20% IBN- 0.5 mL 2 coupling MeCN 0.5M 8 min 1.0 mL CMIMT / MeCN 3 Imidation 0.5M ADIH / MeCN 2.0 mL 6 min 20% Ac2O, 30% 2,6-lutidine / 1.0 mL 4 cap-2 45 s MeCN 20% MeIm / MeCN 1.0 mL General procedure for the 5’-phosphonate deprotection conditions (25 µmole): To prepare TMSI solution for 5’-phosphonate deprotection, pyridine (0.5 mL) was added to DCM (23.9 mL) and the resulting solution was cooled in ice-bath for 15 minutes. 5 After that TMSI reagent (0.6 mL) was added to the mixture to get a bright yellow solution (total volume 25.0 mL). TMSI quenching solution (50 mL) was prepared by adding 2-Dodecane thiol (12.0 mL) and TEA (18.0 mL) in acetonitrile (18.0 mL). After completion of the synthesis, the CPG solid support was dried and transferred into 50 mL plastic tube. Minimum amount of DCM was added to 5’-Phosphonate containing 10 oligonucleotide on CPG and the CPG was vortexed to get a homogenous slurry. To this homogenous slurry, the TMSI solution (10.0 mL) was added slowly and mixed well. After the addition of total TMSI solution the color of the reaction mixture turns yellow indicating excess of TMSI solution. The resulting reaction mixture was stirred for 30 minutes at room temperature. After 30 min. the support was promptly washed using excess of acetonitrile 15 followed by addition of quenching solution (10.0 mL) and this process was repeated three times (Total quenching volume 30.0 mL). The total time of exposure was limited to 20 min. The CPG was rinsed thoroughly using acetonitrile and drying under vacuum. Afterwards, CPG was subjected to standard cleavage and deprotection condition. 20 General procedure for the C&D conditions (25 ^mol scale): After completion of the synthesis and 5’-phosphonate deprotection, the CPG solid support was dried and transferred into 50 mL plastic tube. The CPG was treated with DS1 reagent (2.5 mL; 100 uL / umol) for 3 h at 27 °C, then added conc. NH3(5.0 mL; 200 umol / umol) for 24 h at 37 °C. The reaction mixture was cooled to room temperature and the CPG was 25 separated by membrane filtration, washed with 15 mL of H2O. The crude material (filtrate) was analyzed by LTQ and RP-UPLC. 193 088290.0189 Example 1A. Example alternative procedure for preparation of oligonucleotide compositions (general cycle)^ In some embodiments, preparations include one or more DPSE and / or PSM cycles.^ 5 A number of oligonucleotide compositions were synthesized and assessed, including, e.g., those in the Figures and Tables.^ As described and confirmed herein, technologies of the present disclosure are useful for preparing various compositions of oligonucleotides comprising various structural features at various scales (e.g., 1 µmol, 5 µmol, or 50 µmol). It is understood that certain parameters 10 will be modified based on the scale, e.g., volumes or equivalents.^ In some embodiments, as confirmed herein, provided technologies, e.g., those utilizing chiral auxiliaries comprising electron-withdrawing groups (e.g., RC11comprising electron-withdrawing groups (e.g., −SO2RC1, −C(O)RC1, etc.)) are particularly useful for preparing chirally controlled compositions of oligonucleotides comprising 2’-OH sugars (e.g., sugars with R2s= OH, such 15 as sugars typically found in natural RNA), particularly when such sugars are bonded to chirally controlled internucleotidic linkages.^ The resulting oligonucleotides can undergo an annealing step to form a duplex. Example 1B. Example procedure for preparation of oligonucleotide compositions (1 µmol 20 scale) Certain stereopure oligonucleotides were synthesized at 1 µmol scale using a MerMade192 synthesizer and universal CPG.^ In some embodiments, an amidite approach was used to incorporate GalNAc on the 5’ end.^ Generally, cyanoethyl amidites were used to prepare the PO linkages, DPSE amidites for the PS linkages, and PSM amidites for the PN linkages.^ 25 A typical MerMade192, 1 µmol cycle is outlined in the table below:^ Approx. Step^ Operation^ Reagents and Solvent^ Volume^ Total Time^ 1^ Detritylation^ 3% dichloroacetic acid in toluene^ 5 x 225 µL^ 6.5 min^ 95 µL / 2^ Double 0.1M phosphoramidite in combinations of 110 6 min^(per Coupling^ ACN / IBN / PC / DMF and 0.5M CMIMT in ACN^ µL^(per coupling) coupling) 194 088290.0189 3^ Cap 1^ 80% THF / 10% 2,6-lutidine / 10% acetic anhydride^ 200 µL^ 1.5 min^ Oxidation 0.02M iodine in 70% THF / 20% pyridine / 10% (PO)^ water^ 200 µL^ 1.5 min^ 4^ Sulfurization 0.1M xanthane hydride in 50% pyridine / 50% (PS)^ ACN^ 200 ^ 6.5 min^ PN^ 0.3M ADIH in ACN^ 200 µL^ 7 min^ 5^ Cap 2^ 80% THF / 10% 2,6-lutidine / 10% acetic 100 µL / anhydride and 16% n-methylimidazole in THF^ 100 µL^ . min^ The first step of deprotection was performed on the synthesizer.^ 200 µL of 20% diethylamine in ACN was added to the column for 3 x 6 min followed by washing with ACN and drying.^ CPG was transferred to a container and 250 µL of fluoride solution was added.^ The fluoride solution consisted of dimethylformamide, water, triethylamine trihydrofluoride, 5 and triethylamine (15.5 / 3.1 / 1.0 / 1.8 volume ratio).^ After about 4 hours at room temperature, approximately 375 µL of 30% ammonium hydroxide was added, and the reaction incubated at 37 °C overnight.^ The CPG was filtered and washed with water and the filtrate collected.^ The oligonucleotides were purified by anion exchange purification at room temperature.^ The oligonucleotide was loaded onto a column packed with Source Q15 resin 10 after equilibration with a 20 mM sodium hydroxide in 20% acetonitrile mobile phase.^ The purified oligonucleotide was eluted using a mobile phase of 20 mM sodium hydroxide and 2.5 M sodium chloride in 20% acetonitrile.^ The desired fraction was desalted using a G-25 Sephadex column against water for injection.^ Desalted samples were dried, reconstituted and analyzed. 15 A useful protocol for GalNAc conjugation is described below as an example.^ 195 088290.0189 = oligonucleotide chain For example, pre-conjugation oligo sequence can be represented by the following structure. 5 The tri-antennary GalNAc acid (hydroxyl groups protected as −OAc) can be represented by the following structure The tri-antennary GalNAc acid (hydroxyl groups protected as −OAc) and HATU were 10 weighed out in a 50 mL plastic tube and dissolved in anhydrous acetonitrile then DIEA was added into the tube. The resulting mixture was stirred for 10 min at 37 ºC. Lyophilized pre- 196 088290.0189 conjugation oligo sequence was reconstituted in water in a separate tube and the GalNAc mixture was added to the oligonucleotide solution and stirred for 60 min at 37 ºC. The reaction was monitored by RP-UPLC. Reaction was complete in 1 hr. The reaction mixture was concentrated under vacuum to remove the acetonitrile and the resultant GalNAc-conjugated 5 oligonucleotides is treated with conc. ammonia for 2 hr at 37ºC. The formation of final product was confirmed by mass spectrometry and RP-UPLC. The conjugated material was purified by anion exchange chromatography and desalted using tangential flow filtration (TFF) to obtain the final product. Additional chemical moieties can also be installed by coupling with phosphoramidites 10 comprising such additional chemical moieties (and optional linkers), e.g., phosphoramidites comprising GalNAc such as those described in Example 1C.^ Additional technologies for preparing oligonucleotides are illustrated below as examples.^ Example 1C. Example procedure for preparation of oligonucleotide compositions (50 15 µmol scale) Certain stereopure oligonucleotides were synthesized at 50 µmol scale using a MerMade12 synthesizer and standard CPG.^ In some embodiments, an amidite approach was used to incorporate GalNAc on the 5’ end.^ Generally, cyanoethyl amidites were used to prepare the PO linkages, DPSE amidites for the PS linkages and PSM amidites for the PN linkages.^ A 20 typical MerMade12, 50 µmol cycle is outlined in the table below:^ Approx. Step^ Operation^ Reagents and Solvent^ Volume^ Total Time^ 1^ Detritylation^ 3% dichloroacetic acid in toluene^ 4 x 4.5 ^ 5 min^ 2^ Single 0.15M phosphoramidite in combinations of 15 mL / Coupling^ ACN / IBN / PC and 0.5M CMIMT in ACN^ 2.25 mL^ 6-12 min^ 3^ Cap 1^ 80% THF / 10% 2,6-lutidine / 10% acetic anhydride^ 5 mL^ 1 min^ Oxidation 0.02M iodine in 70% THF / 20% pyridine / 10% (PO)^ water^ 6 mL^ 2-4 min^ 4^ Sulfurization 0.1M xanthane hydride in 50% pyridine / 50% (PS)^ ACN^ 6 mL^ 6 min^ PN^ 0.3M ADIH in ACN^ 6 mL^ 10 min^ 5^ Cap 2^ 80% THF / 10% 2,6-lutidine / 10% acetic 2.5 mL / anhydride and 16% n-methylimidazole in THF^ 2.5 mL^ 1min^ CMIMT: N-cyanomethylimidazolium triflate; ACN: acetonitrile; IBN: isobutyronitrile; ADIH: 2-azido-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate; THF: 197 088290.0189 tetrahydrofuran; PC: propylene carbonate.^ The cycles were performed multiple times until the desired length was achieved.^ In some embodiments, an amidite approach was used to incorporate GalNAc on the 5’ 5 end. The GalNAc amidite, or tri-antennary GalNAc-acetyl derivative C6 phosphoramidite, can be represented by the following structure. The synthesis is disclosed in WO2023201095 (Paragraph [001468]) 10 The GalNAc amidite was coupled either as a single 10-15 min or a two x 10 min procedure.^ For each coupling, 1.5 mL of 0.2M GalNAc amidite and 3 mL of CMIMT in ACN were added.^^ The first step of deprotection was performed on the synthesizer.^ 6 mL of 20% 15 diethylamine in ACN was added to the column for 10 min followed by washing with ACN and drying.^ CPG was transferred to a tube and 5 mL of fluoride solution was added.^ The fluoride solution consisted of dimethylsulfoxide, water, triethylamine trihydrofluoride, and triethylamine (15.5 / 3.1 / 1.0 / 1.8 volume ratio).^ After about 1 hour at room temperature, approximately 10 mL of 30% ammonium hydroxide was added, and the reaction incubated at 20 37°C overnight.^ The CPG was filtered off and washed with water and the filtrate collected.^ The oligonucleotides were purified by anion exchange purification at room temperature.^ The oligonucleotide was loaded onto a column packed with Source Q15 resin after equilibration with a 20 mM sodium hydroxide in water or 20 mM sodium hydroxide with 20% acetonitrile in water mobile phase.^ The purified oligonucleotide was eluted as fractions 25 by gradient elution with a mobile phase of 20 mM sodium hydroxide and 2.5 M sodium 198 088290.0189 chloride in water or 20 mM sodium hydroxide and 2.5 M sodium chloride with 20% acetonitrile in water.^ Fractions were analyzed, pooled to the desired purity and desalted using a G-25 Sephadex column against water for injection.^ Desalted samples were dried, reconstituted and sterile filtered prior to final analysis including UPLC, LC-MS and UV-Vis. 5 199 088290.0189 The contents of pages 724-932 of WO 2024 / 182749 are incorporated herein by reference in their entirety, wherein the synthesis of the following compounds is described:WV- NU-017, WV-NU-010, WV-NU-10-CNE, WV-NU-128, WV-NU-128-CNE, WV-NU-038, WV-NU-037, WV-NU-037A, WV-NU-037, WV-NU-040, WV-NU-042, WV-RA-009, WV- 5 RA-009-CNE, WV-RA-010, WV-RA-010-CNE, 5’-(R)-C-M’-5'-ODMT’-2'-F-dU, 5’-(R)-C- M’-5'-ODMT’-2'-F-dU-CNE phosphoramidite, 5'-(S)-C-Me-5'-ODMTr-2'-F-dU, of 5'-(R)-C- Me-5'-ODMTr-2'-OMe-U, 5'-(S)-C-Me-5'-ODMTr-2'-OMe-U, 5'-(R)-C-Me-5'-ODMTr-dT, 5'-(S)-C-Me-5'-ODMTr-dT, L-DPSE-Cl, (3’-L-DPSE-WV-NU-010), 3’-L-DPSE-WV-NU- 017, 3’-L-DPSE-WV-NU-040, 3’-L-DPSE-WV-NU-037, 3’-L-DPSE-WV-NU-037A, L- 10 DPSE-5’-ODMTr-5’-(R)-Me-2’F-dU amidite, L-DPSE-5’-ODMTr-5’-(S)-Me-2’F-dU amidite, 3’-L-DPSE-WV-RA-009, D-DPSE-Cl, 3’-D-DPSE-5’-ODMTr-5’-(R)-Me-dT amidite, 3’-D-DPSE-5’-ODMTr-5’-(S)-Me-dT amidite, 3’-D-DPSE-5'-ODMTr-5’-(R)-Me- 2'F-dU amidite, 3’-D-DPSE-5'-ODMTr-5’-(S)-Me-2'F-dU amidite, 3’-D-DPSE-5’-PO(OEt)2 Vinylphosphonate-dT amidite, 3’-D-DPSE-5’-(R)-Me-PO(OEt)2-dT amidite, 3’-D-DPSE-5’-15 (S)-Me-PO(OEt)2-dT amidite, WV-NU-231, WV-NU-306, WV-NU-299, WV-NU-301, L- DPSE-2’-OMe-5’-(R)-Me-PO(OEt)2-uridine amidite, L-DPSE-2’-OMe-5’-triazole- PO(OEt)2-uridine amidite, D-DPSE-2’-OMe-5’-triazole-PO(OEt)2-2’OMe-uridine amidite, L-DPSE-2’-OMe-5’-vinyl-PO(OEt)2-uridine amidite, D-DPSE-2’-OMe-5’-vinyl-PO(OEt)2- uridine amidite, L-PSM-2’-O-C16 lipid-5’-ODMTr-uridine amidite, D-PSM-2’-O-C16 lipid-20 5’-ODMTr-uridine amidite, 5’-(R)-C-Me-5’-ODMTr-2’OMe-A(Bz)-D-PSM, 5’-(S)-C-Me-5’- ODMTr-2’OMe-A(Bz)-D-PSM, 2’O-C16-U-L-PSM, 2’O-C16-U-D-PSM, 2’-OMe-5’- triazole-PO(OEt)2-3’-CNE uridine amidite, 2’-O-C16 lipid-5’-ODMTr-3’-CNE Uridine amidite, 5’-(R)-C-Me-5’-ODMTr-2’OMe-A(Bz)-CNE, 5’-(R)-C-Me-5’-ODMTr-2’Fd-A(Bz)- CNE, 5’-(R)-C-Me-5’-ODMTr-2’Fd-U-CNE, 5’-ODMTr-(S)-GNA-G(iBu)-CNE, 5’-25 ODMTr-(S)-GNA-T-CNE, 5’-triazole-PO(OEt)2-2’OMe-U-CNE, 2’O-C16-U-CNE, WV- NU-332, WV-NU-306, WV-NU-336, 5’-triazole-PO(OEt)2-2’OMe-U-L-DPSE, 5’-triazole- PO(OEt)2-2’OMe-U-D-DPSE, 5’-vinyl-PO(OEt)2-2’OMe-U-L-DPSE, 5’-vinyl-PO(OEt)2- 2’OMe-U-D-DPSE, WV-NU-223, WV-NU-286, WV-NU-287, WV-NU-288, WV-DL-045 (n009), SOPL-WLS-41 (n033), SOPL-WLS-97 (n039), SOPL-WLS-42 (n040), SOPL-WLS- 30 70, SOPL-WLS-96 (n071), SOPL-WLS-95, and SOPL-WLS-94 (n069). Synthesis SOPL-WLS-98 (n077) Azide. 200 088290.0189 To an ice cool solution of 2-Imidazolidone (25 g, 0.290 mol) in dry 1,4 dioxane (325 mL, 13 5 vol.) was added sodium hydride (60% dispersion in mineral oil) (19 g, 0.494 mol.) portion- wise over a period of 15 min. then the solution was allowed to heat to 65oC for 2 h. After that the mixture was again cool to 0oC and methyl iodide (33.49 mL, 0.537 mol) was added dropwise over a period of 30 mins and stirred at rt for 24 h. Progress of the reaction was monitored by TLC. Then reaction mixture was diluted with ice water (100 mL) and extracted 10 with ethyl acetate (2 x 200 mL), washed with brine (1 x 150 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography over silica-gel (230-400 mesh) eluted in 2% MeOH / DCM afforded SOPL- WLS-98A as a off white solid (9 g, 31%). TLC Mobile phase details: 7% MeOH in DCM. 2. Preparations of 1-docosyl-3-methylimidazolidin-2-one (SOPL-WLS-98-04) 15 To a stirred solution of (SOPL-WLS-98A) (9 g, 0.0918 mol) in dry toluene (180 mL, 20 vol.) was added KOH powder (20.5 g, 0.3673 mol.), anhydrous free flow K2CO3 (2.53 g, 0.0183 mol.), followed by TBAB (1.47 g, 0.0183 mol.) at rt. Then reaction mixture was further stirred at rt for 20 min. Then added 1-bromodocosane (70 mL, 0.183 mol) dropwise over a period of 20 30 mins at 0oC and further stirred at 80oC for 18 h. Progress of the reaction was monitored by TLC. The crude was diluted ice water (150 mL), extracted with DCM (100 mL x 3), washed with water (80 mL x 1), dried over Na2SO4 and concentrated under reduced pressure. The crude 201 088290.0189 was purified by column chromatography over silica-gel (230-400 mesh) eluted in 4% MeOH / DCM to get an off white solid (SOPL-WLS-98A) (25.3 g, 68%). TLC Mobile phase details: 7% MeOH in DCM.1H NMR (400 MHz, CDCl3): δ in ppm = 3.27 (s, 4H), 3.16 (t, 2H, J1 = 7.2 Hz), 2.78 (s, 3H), 1.48 (t, 2H, J1 = 6.9 Hz), 1.28-1.25 (m, 42H), 0.88 (t, 3H, J1 = 6.9 5 Hz). MS: m / z calcd for C26H52N2O, 408.7; found 409.66 [M+H]+. 3. Preparations of 2-chloro-1-docosyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumchloride (SOPL-WLS-98-05) To a stirred solution of (SOPL-WLS-98-04) (20 g, 0.049 mol) in dry toluene (400 mL, 20 vol.) 10 was added Oxalyl chloride (63 mL, 0.735 mol) dropwise over a period for 30 min, at 0oC. Then reaction mixture was further stirred at 60oC for 3days. Progress of the reaction was monitored by TLC. Then reaction mixture was concentrated under reduced pressure. The crude was washed with diethyl ether (100 mL x 2), dried under vacuum afforded a yellowish syrup.(SOPL-WLS-98-05) (25 g, crude). TLC Mobile phase details: 7% MeOH in DCM.1H NMR15 (400 MHz, CDCl3): δ in ppm = 6.01 (s, 4H), 4.34 (t, 2H, J1 = 9.6 Hz), 4.25 (t, 2H, J1 = 10.0 Hz), 3.61 (t, 2H, J1 = 7.6 Hz), 3.33 (s, 3H), 3.18 (t, 1H, J1 = 7.2 Hz), 2.81 (s, 1H), 1.66 (s, 2H), 1.47 (t, 1H, J1 = 7.2 Hz), 1.29-1.26 (m, 51H), 0.86 (t, 4H, J1 = 6.9 Hz). MS: m / z calcd for C26H52Cl2N2, 428.2; found 428.87 [M+]+.20 4. Preparations of 2-chloro-1-docosyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate(V) (SOPL-WLS-98-06) To a stirred solution of (SOPL-WLS-98-05) (25 g, 0.0539 mol) in DCM (150 mL, 6 vol.) was 25 added a solution of KPF6(9.9 g, 0.0539 mol.) in water (87.5 mL, 3.5 vol.) dropwise over a period of 30 mins at 0oC. Above reaction mixture was stirred at rt for 3 h. Progress of the reaction was monitored by TLC. Then the mixture was filtered through a celite bed washed 202 088290.0189 with DCM (2 x 60 mL) and organic layer washed with water (2 x 60 mL), dried over Na2SO4and concentrated under reduced pressure. The crude was washed with diethyl ether (100 ml x 3) and dried under vacuum afforded SOPL-WLS-98-06 as off white solid ( (23 g, 74%). TLCMobile phase details: 7% MeOH in DCM.1H NMR (400 MHz, CDCl3): δ in ppm = 4.16-4.025 (m, 4H), 3.53 (t, 2H, J1 = 7.6 Hz), 3.24 (s, 3H), 1.65-1.62 (m, 2H), 1.2 (d, 40H, J1 = 24.9 Hz), 0.86 (t, 3H, J1 = 6.8 Hz). MS: m / z calcd for C24H52ClF6N2P, 428.2; found 428.2 [M+]. 5. Preparations of 2-azido-1-docosyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate(V)) (SOPL-WLS-98) SOPL-WLS-98 To a stirred solution of (SOPL-WLS-98-06) (23 g, 0.0401 mol) in dry acetonitrile (230 mL, 15 10 vol.) was added sodium azide (3.91 g, 0.0602 mol.) portion-wise over a period of 10 mins at 0oC and further stirred at rt for 3 h. Progress of the reaction was monitored by TLC. Then reaction mixture was filtered through a celite bed washed with acetonitrile (2 x 50 mL) and concentrated under reduced pressure. The crude was washed with diethyl ether (100 ml x 2) and dried under vacuum afforded SOPL-WLS-98 as an off white solid (18 g, 77%). TLC20 Mobile phase details: 7% MeOH in DCM.1H NMR (400 MHz, CDCl3): δ in ppm = 3.99-3.84(m, 4H), 3.40 (t, 2H, J1 = 7.6 Hz), 3.21 (s, 3H), 1.61 (t, 2H, J1 = 6.9 Hz), 1.27 (d, 38H, J1 = 16.9 Hz), 0.88 (t, 3H, J1 = 6.8 Hz). MS: m / z calcd for C26H52F6N5P; 434.7; found 435.0 [M+H]+. IR: 2176.27. 25 Synthesis of WV-DL-85 (n082) Azide. 203 088290.0189 1. Preparations of 1-decyl-3-methylimidazolidin-2-one (WV-DL-85B) To a stirred solution of (WV-DL-85A) (10 g, 0.1 mol) in dry THF (300 mL, 30 vol.) was added KOH powder (22.44 g, 0.4 mol.), K2CO3 (2.76 g, 0.02 mol.), followed by TBAB (1.61 g, 0.005 5 mol) at rt. Then reaction mixture was further stirred at rt for 20 min. Then added 1- bromodecane (41.3 mL, 0.2 mol) dropwise over a period of 30 mins at 0oC and stirred at 65oC for 18 h. Progress of the reaction was monitored by TLC. The crude was diluted with ice water (100 mL), extracted with EtOAc (100 mL x 2), washed with water (70 mL x 2), dried over Na2SO4and concentrated under reduced pressure. The crude compound was purified by 10 column chromatography over silica-gel (230-400 mesh) eluted in 4% MeOH in DCM concentrated under reduced pressure afforded WV-DL-85B as Oily liquid (20 g, 74%). TLC Mobile phase details: 5% MeOH in DCM. 1H NMR (500 MHz, CDCl3): δ in ppm = 3.26 (s, 4H), 3.16 (t, 2H, J1 = 7.6 Hz), 2.77 (s, 3H), 1.48 (q, 2H, J1 = 7.3 Hz), 1.27 (d, 14H, J1= 17.9 Hz), 0.87 (t, 3H, J1 = 6.9 Hz). MS: m / z calcd 15 for C14H28N2O, 240.4; found 241.43 [M+H] +. 2. Preparations of 2-chloro-1-decyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumchloride(WV-DL-85C) 20 To a stirred solution of (WV-DL-85B).) (18 g, 0.075 mol) in dry toluene (360 mL, 20 vol) was added oxalyl chloride (96 mL, 1.13 mol) dropwise over a period for 30 min, at 0oC. Then reaction mixture was further stirred at 60oC for 3 days. Progress of the reaction was monitored by TLC. Then reaction mixture was concentrated under reduced pressure. The crude was codistilled with toluene (100 ml x 2). The crude was washed with diethyl ether (100 mL x 2), 25 dried under vacuum to give a brown solid (WV-DL-85C) (19 g, crude). TLC Mobile phase details: 7% MeOH in DCM. 1H NMR (500 MHz, CDCl3): δ in ppm = 10.26 (s, 2H), 4.35 (m,2H), 4.26 (m, 2H), 3.61 (t, 2H, J1 = 7.6 Hz), 3.34 (s, 3H), 1.68 (s, 2H, J1= 7.2 Hz) , 1.29 (m, 14H), 0.88 (t, 3H, J1 = 6.9 Hz). MS: m / z calcd for C14H28Cl2N2, 295.3; found 260.24 [M-Cl]. 204 088290.0189 3. Preparations of 2-chloro-1-decyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate(V) (WV-DL-85D) 5 To a stirred solution of crude (WV-DL-85C) (18.5 g, 0.063 mol) in DCM (110 mL, 6 vol) was added a solution of KPF6(11.5 g, 0.063 mol.) in water (64.7 mL, 3.5 vol) drop wise over a period of 30 mins at 0oC. Above reaction mixture was stirred at rt for 4 h. Progress of the reaction was monitored by TLC. To the above reaction mixture was added DCM (90 ml) and H2O (45 ml), separate two layers, organic layer washed with water (2 x 90 mL), dried over 10 Na2SO4 and concentrated under reduced pressure. The crude was washed with diethyl ether (90 ml x 3) and dried under vacuum and obtain WV-DL-85D an off white solid (18g, 71%). TLC Mobile phase details: 5% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 4.0 (m,4H), 3.49 (m, 2H), 3.21 (s, 3H), 1.65 (m, 2H), 1.25 (m, 14H), 0.88 (t, 3H, J1 = 7.2 Hz). MS: m / z calcd for C14H28ClF6N2P, 404.8; found 259.8 [M+]. 15 4. Preparations of 2-azido-1-decyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluorophosphate (V) (WV-DL-85) To a stirred solution of (WV-DL-85D) (19 g, 0.044 mol) in acetonitrile (180 mL, 10 vol) was 20 added sodium azide (4.34 g, 0.066 mol) portion-wise over a period of 20 mins at 0oC and further stirred at rt for 5 h. Progress of the reaction was monitored by TLC. Then reaction mixture was filtered through a celite bed, washed with acetonitrile (2 x 80 mL) and concentrated under reduced pressure to afford a yellowish solid .The solid was washed with diethyl ether (100 ml x 4) and dried under vacuum to give an off white solid (WV-DL-85) (1625 g, 82%). TLC Mobile phase details: 100% EtOAc.1H NMR (500 MHz, CDCl3): δ in ppm =3.96 (m, 2H), 3.86 (m, 2H), 3.38 (t, 2H, J1 = 7.6 Hz), 3.20 (s, 3H), 1.63 (t, 2H, J1 = 7.2 Hz), 1.28 (m, 14H), 0.88 (t, 3H), MS: m / z calcd for C14H28F6N5P; 266.4; found 266.53([M+]). 205 088290.0189 Synthesis of WV-DL-86 (n083) Azide. 5 WV-DL-86B To a stirred solution of (WV-DL-86A) (8 g, 0.08 mol) in dry THF (240 mL, 30 vol) was added KOH powder (17.9 g, 0.32 mol), K2CO3 (2.2 g, 0.016 mol), followed by TBAB (1.28 g, 0.004 mol) at rt. Then reaction mixture was further stirred at rt for 20 min. Then added 1- 10 bromotetradecane (47.6 mL, 0.16 mol) dropwise over a period of 40 mins at 0oC and stirred at 65oC for 22 h. Progress of the reaction was monitored by TLC. The crude was diluted with ice water (100 mL), extracted with EtOAc (100 mL x 2), washed with water (100 mL x 1), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica-gel (230-400 mesh) eluted in 4% MeOH in DCM 15 concentrated under reduced pressure afforded WV-DL-86B as a liquid (18 g, 76%). TLC Mobile phase details: 5% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 3.25 (s, 4H), 3.14 (t, 2H, J1 = 7.6 Hz), 2.76 (s, 3H), 1.46 (t, 2H, J1 = 6.9 Hz), 1.27 (s, 7H), 1.23 (s, 15H), 0.88 (t, 3H, J1 = 6.9 Hz). MS: m / z calcd for C18H36N2O, 296.5; found 297.56 [M+H] +. 20 2. Preparations of 2-chloro-1-tetradecyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumchloride (WV-DL-86C) 206 088290.0189 To a stirred solution of (WV-DL-86B) (14 g, 0.047 mol) in dry toluene (280 mL, 20 vol) wasadded oxalyl chloride (60 mL, 0.71 mol) dropwise over a period for 30 min, at 0oC. Then the reaction mixture was further stirred at 60oC for 80 h. Progress of the reaction was monitored by TLC. Then reaction mixture was concentrated under reduced pressure. The crude was co- 5 distilled with toluene (100 ml x 2). The crude was washed with diethyl ether (100 mL x 2), dried under vacuum to give brown solid (WV-DL-86C) (18 g, crude). TLC Mobile phase details: 7% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 4.31 (ddd, 4H, J1 = 44.8Hz, J2 = 11.7 Hz), 3.62 (t, 2H, J1 = 7.6 Hz), 3.35 (s, 3H), 1.69 (d, 2H, J1 = 6.9 Hz) , 1.29 (m, 22H), 0.88 (t, 3H, J1 = 6.9 Hz). MS: m / z calcd for C18H36Cl2N2, 351.4; found 316.34 [M-Cl]. 10 3. Preparations of 2-chloro-1-tetradecyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate(V) (WV-DL-86D) To a stirred solution of crude (WV-DL-86C) (16 g, 0.0455 mol) in DCM (96 mL, 6 vol) was 15 added a solution of KPF6(8.3 g, 0.046mol.) in water (56 mL, 3.5 vol.) drop wise over a period of 30 mins at 0oC. Above reaction mixture was stirred at rt for 4 h. Progress of the reaction was monitored by TLC. To the above reaction mixture was added DCM (100 ml) and H2O (50 ml), separate two layers, organic layer washed with water (2 x 100 mL), dried over Na2SO4and concentrated under reduced pressure. The crude was washed with diethyl ether (100 ml x 3) 20 and dried under vacuum afforded WV-DL-86D an off white solid (16g, 76%). TLC Mobile phase details: 5% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 4.10 (m, 4H), 3.53(t, 2H, J1 = 7.6 Hz), 3.24 (s, 3H), 1.66 (d, 2H, J1=6.9 Hz), 1.28 (t, 22H, J1 = 13.4 Hz), 0.88 (t, 3H, J1 = 7.2 Hz). MS: m / z calcd for C18H36ClF6N2P, 315.9; found 316.37 [M+].25 4. Preparations of 2-azido-1-tetradecyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate (V) (WV-DL-86) 207 088290.0189 To a stirred solution of (WV-DL-86D) (16 g, 0.0326 mol) in acetonitrile (160 mL, 10 vol) was added sodium azide (3.37 g, 0.049 mol) portion-wise over a period of 20 mins at 0oC and further stirred at rt for 4 h. Progress of the reaction was monitored by TLC. Then reaction mixture was filtered through a celite bed, washed with acetonitrile (2 x 60 mL) and 5 concentrated under reduced pressure to afford a yellowish solid .The solid was washed with diethyl ether (100 ml x 4) and dried under vacuum to furnish an off white solid. (WV-DL-86) (14 g, 86%). TLC Mobile phase details: 100% EtOAc.1H NMR (500 MHz, CDCl3): δ in ppm= 3.96 (m, 2H), 3.86 (m, 2H), 3.39 (t, 2H, J1 = 7.6 Hz), 3.20 (s, 3H), 1.62 (q, 2H, J1 = 7.1 Hz), 1.28 (d, 22H), 0.88 (t, 3H, J1 = 6.9 Hz) MS: m / z calcd for C18H36F6N5P; 322.5; found:10 322.74([M+]). Synthesis of WV-DL-90 (n084) Azide 1. Preparation of 1-octadecyl-3-methylimidazolidin-2-one (WV-DL-90B)15 To a stirred solution of (WV-DL-90A) (10 g, 0.1 mol) in dry THF (300 mL, 30 vol) was added KOH powder (22.4 g, 0.4 mol), K2CO3 (2.76 g, 0.02 mol), followed by TBAB (1.61 g, 0.005 mol) at rt. Then the reaction mixture was further stirred at rt for 30 min. after that was added 1-bromooctadecane (68.3 mL, 0.2 mol) dropwise over a period of 30 mins at 0oC and stirred at 20 65oC for 21 h. Progress of the reaction was monitored by TLC. The crude was diluted with ice water (100 mL), extracted with EtOAc (100 mL x 3), washed with water (80 mL x 2), dried over Na2SO4and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica-gel (230-400 mesh) eluted in 4% MeOH in DCM concentrated under reduced pressure to give WV-DL-90B as a liquid material (22 g, 62%). 25 TLC Mobile phase details: 5% MeOH in DCM.1H NMR (400 MHz, CDCl3): δ in ppm = 3.27 208 088290.0189 (s, 4H), 3.16 (t, 2H, J1 = 7.4 Hz), 2.78 (s, 3H), 1.49 (q, 2H, J1 = 7.0 Hz), 1.27 (d, 30H, J1 = 14.4 Hz), 0.88 (m, 3H). MS: m / z calcd for C22H44N2O, 352.6; found 353.71 [M+H] +. 2. Preparation of 2-chloro-1-octadecyl-3-methyl-4,5-dihydro-1H-imidazol-3-ium5 chloride (WV-DL-90C) To a stirred solution of (WV-DL-90B) (10 g, 0.28 mol) in dry toluene (200 mL, 20 vol) wasadded oxalyl chloride (36.6 mL, 0.43 mol) dropwise over a period for 30 min, at 0oC. Then reaction mixture was further stirred at 60oC for 3days. Progress of the reaction was monitored10 by TLC. Then reaction mixture was concentrated under reduced pressure. The crude was co- distilled with toluene (100 ml x2). The crude was washed with diethyl ether (100 mL x 2), dried under vacuum to give WV-DL-90C as brown solid (12 g, crude). TLC Mobile phase details: 7% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 4.31 (dt, 2H, J1 = 4.7 Hz), 3.62 (t, 2H, J1 = 7.6 Hz), 3.35 (s, 3H), 1.67 (s, 2H) , 1.29 (d, 33H, J1= 31.0 Hz), 0.88 (t, 3H, J1 = 15 6.9 Hz). MS: m / z calcd for C22H44Cl2N2, 406.7; found 372.7 [M-Cl]. 3. Preparation of 2-chloro-1-octadecyl-3-methyl-4,5-dihydro-1H-imidazol-3-iumhexafluoro phosphate(V) (WV-DL-90D) 20 To a stirred solution of (WV-DL-89C) (12 g, 0.029 mol) in DCM (72 mL, 6 vol) was added a solution of KPF6(5.4 g, 0.029 mol) in water (42 mL, 3.5 vol) drop wise over a period of 30 mins at 0oC. Above reaction mixture was stirred at rt for 4 h. Progress of the reaction was monitored by TLC. To the above reaction mixture added DCM (100 ml) and H2O (50 ml), separate two layers, organic layer washed with water (2 x 100 mL), dried over Na2SO4and 25 concentrated under reduced pressure. The crude was washed with diethyl ether (100 ml x 3) and dried under vacuum to afforded WV-DL-89D as off white solid (11 g, 79%). TLC Mobile phase details: 5% MeOH in DCM.1H NMR (500 MHz, CDCl3): δ in ppm = 4.10 (m, 4H), 3.52209 088290.0189 (t, 2H, J1 = 7.6 Hz), 3.24 (s, 3H), 1.65 (t, 2H, J1=6.9 Hz), 1.28 (t, 30H, J1 = 13.8 Hz), 0.88 (t, 3H, J1 = 6.9 Hz). MS: m / z calcd for C22H44ClF6N2P, 372.1; found 372.45 [M+]. 4. Preparation of 2-azido-1-hexadecyl-3-methyl-4,5-dihydro-1H-imidazol-3-5 iumhexafluorophosphate (V) (WV-DL-90) To a stirred solution of (WV-DL-89D) (11 g, 0.021 mol) in acetonitrile (110 mL, 10 vol) was added sodium azide (2.1 g, 0.032 mol) portion-wise over a period of 20 mins at 0oC and further stirred at rt for 4 h. Progress of the reaction was monitored by TLC. Then reaction mixture was 10 filtered through a celite bed washed with acetonitrile (2 x 100 mL) and concentrated under reduced pressure to afford a light yellow solid. The solid was washed with diethyl ether (100 ml x 4) and dried under vacuum to give WV-DL-89 as an off white solid (10 g, 89%). TLC Mobile phase details: 100% EtOAc.1H NMR (500 MHz, CDCl3): δ in ppm = 3.96 (m, 2H),3.86 (m, 2H), 3.39 (t, 2H, J1 = 7.6 Hz), 3.20 (s, 3H), 1.61 (t, 2H, J1 = 7.6 Hz), 1.28 (m, 30H), 15 0.88 (t, 3H, J1 = 6.9 Hz), MS: m / z calcd for C22H44F6N5P; 378.6; found 379.05([M+]). EXAMPLE 1D. Synthesis of WV-NU-347 20 General Scheme: 210 088290.0189 WV-NU-347 2'-Fluoro-5'-PO(POM)2-Triazolyl Phosphonate Uridine (WV-NU-347) 5 Experimental Procedure: 1. Preparation of compound 2C： 10 For three batches: To a solution of compound 1C (36 g, 249.15 mmol) in THF (400 mL) was added bromo(ethynyl)magnesium (0.5 M, 498.29 mL) under N2. The mixture was stirred at 0- 25 °C for 2 hr. TLC indicated compound 1C was consumed completely and one new spot formed. Each reaction mixture was quenched by addition NH4Cl 100mL at 0 °C, and then diluted with water 300 mL and extracted with EtOAc (100 mL * 3). The combined organic 15 layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0:1). Compound 2C (28.5 g, 28.44% yield) was obtained as a yellow oil. TLC: Petroleum ether : Ethyl acetate = 0:1, Rf = 0.35211 088290.0189 2. Preparation of compound 5A： 5 For three batches: To a solution of compound 2C (9.5 g, 70.86 mmol) in ACN (500 mL) was added 4A MS (3 g, 70.86 mmol), iodomethyl 2,2-dimethylpropanoate (68.61 g, 283.43 mmol). The mixture was stirred at 82 °C for 15 hr. TLC indicated Reactant 1 was consumed completely and two new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 10 Petroleum ether: Ethyl acetate = 10:1 to1:1). Compound 5A (45 g, 63.32% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.72 (d, J = 1.2 Hz, 2H), 5.68 (s, 2H), 3.04 (d, J = 14.3 Hz, 1H), 1.22 (s, 18H) 31P NMR (162 MHz, CHLOROFORM-d) δ = -10.36 (s, 1P) 15 TLC: Petroleum ether : Ethyl acetate = 3:1, Rf = 0.38 3. Preparation of compound 2: 20 For three batches. To a solution of compound 1 (15 g, 60.93 mmol) in THF (210 mL) was added imidazole (10.78 g, 158.41 mmol), I2 (24.74 g, 97.48 mmol) and PPh3 (25.57 g, 97.48 mmol) at 0 °C. The mixture was stirred at 25 °C for 4 hr. LCMS showed compound 1 was consumed completely and the desired mass was detected. Three batches with together. The reaction was quenched by 10% aqueous sodium thiosulfate solution (100 ml). After removing 25 the solvent and volatiles under reduced pressure, the residue was extracted into EtOAc (50 mL * 5) and washed with saturated aqueous NaHCO3solution. The organic layer was separated, 212 088290.0189 dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1 to Dichloromethane: Methanol =1: 0 to 3: 1). The crude product was purified by re-crystallization from Ethyl acetate (100 mL) and Methanol (10 mL) at 15 °C. Compound 2 (43 g (total three batches), 66.15% 5 yield,) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.46 (br s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 5.94 - 5.79 (m,2H), 5.66 (d, J = 8.0 Hz, 1H), 5.33 - 5.13 (m, 1H), 4.10 - 3.98 (m, 1H), 3.77 (dt, J = 3.4, 7.2 Hz, 1H), 3.60 (dd, J = 3.6, 11.0 Hz, 1H), 3.41 (dd, J = 6.8, 11.0 Hz, 1H) 19F NMR (376 MHz, DMSO-d6) δ = -199.11 (s, 1F) 10 LCMS (M+H+): 356.9, purity: 95.16% TLC: Dichloromethane: Methanol = 10:1 Rf =0.45 4. Preparation of compound 3: 15 For two batches. To a solution of compound 2 (10 g, 28.08 mmol) in 1, 2-dimethoxyethane (100 mL) and H2O (20 mL) was added NaN3(1.83 g, 28.08 mmol) at 0 °C under N2. The mixture was stirred at 90 °C for 12 hr. LCMS showed compound 2 was remained and the desired mass was detected. Two batches with together. The reaction was quenched by H2O 20 (50 mL), and extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated aqueous NaCl 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). The crude product was purified by re- crystallization from Ethyl acetate (100 mL) at 20 °C. Compound 3 (28 g, 85.63% yield) was 25 obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.45 (br s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 5.90 - 5.81 (m, 1H), 5.75 (br s, 1H), 5.66 (d, J = 8.0 Hz, 1H), 5.29 - 5.10 (m, 1H), 4.31 - 4.17 (m, 1H), 3.94- 3.93 (m, 1H), 3.79 - 3.48 (m, 2H) 19F NMR (376 MHz, DMSO-d6) δ = -198.74 (s, 1F) 213 088290.0189 LCMS: (M+H+): 272.0, purity: 92.29%TLC: Dichloromethane: Methanol = 10:1, Rf = 0.45 5. Preparation of WV-NU-347: 5 For two batches. To a solution of compound 3 (5 g, 18.44 mmol) and compound 5A (7.40 g, 22.12 mmol) in H2O (25 mL) and THF (25 mL) was degassed and purged with N2for 3 times, CuSO4.5H2O (5.52 g, 22.12 mmol), sodium ascorbate (4.38 g, 22.12 mmol) was added. The 10 mixture was stirred at 65 °C for 3 hr under N2 atmosphere. LCMS showed compound 3 was consumed completely and the desired mass was detected. Two batches with together. The reaction mixture was extracted with Ethyl acetate (30mL*3). The combined organic layers were washed with saturated aqueous NaCl 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography 15 (SiO2, Petroleum ether: Ethyl acetate=1:0 to 0:1 to Ethyl acetate: Methanol=1:0 to 2:1). Compound WV-NU-347 (14.5 g, 65.91% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.87 - 5.78 (m, 1H), 5.69 (d, J = 13.8 Hz, 4H), 5.62 (dd, J = 2.0, 8.1 Hz, 1H), 5.31 - 5.09 (m, 1H), 4.91 - 4.71 (m, 2H), 4.30 - 4.16 (m, 2H), 1.08 (s, 18H) 2031P NMR (162 MHz, DMSO-d6) δ = 7.04 (s, 1P) 19F NMR (376 MHz, DMSO-d6) δ = -199.16 (s, 1F) LCMS (M+H+): 606.2, purity: 98.32% TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.55 25 EXAMPLE 1E. Synthesis of WV-NU-348 214 088290.0189 (((1-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-(2- methoxyethoxy)tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4- 5 yl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (WV-NU-348) General Scheme: 10 Experimental Procedure: 1. Preparation of compound 2C：215 088290.0189 For four batches: To a solution of compound 1C (36 g, 249.15 mmol, 26.87 mL) in THF (400 mL) was added bromo(ethynyl)magnesium (0.5 M, 498.29 mL) under N2. The mixture was 5 stirred at 0 ~ 25 °C for 2 h. TLC indicated compound 1C was consumed completely and one new spot formed. Four batches with together, the each reaction mixture was quenched by addition NH4Cl 100 mL at 0 °C, and then diluted with water 300 mL and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography 10 (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1). Compound 2C (23 g, 17.21% yield) was obtained as a yellow oil 1H NMR (400 MHz, CHLOROFORM-d) δ = 3.82 (s, 3H), 3.80 (s, 3H), 2.96 (d, J = 13.4 Hz, 1H) 31P NMR (162 MHz, CHLOROFORM-d) δ = -5.07 - -5.22 (m, 1P) 15 TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.31 2. Preparation of compound 5A： 20 For two batches: To a solution of compound 2C (11.5 g, 85.78 mmol) in ACN (500 mL) was added 4A MS (5 g, 85.78 mmol), iodomethyl 2,2-dimethylpropanoate (83.05 g, 343.10 mmol). The mixture was stirred at 82 °C for 15h. TLC indicated compound 2C was consumed completely and two new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography 25 (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1). Compound 5A (33 g, 57.89% yield) was obtained as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.70 (d, J = 1.5 Hz, 2H), 5.66 (d, J = 0.8 Hz, 2H), 3.06 (d, J = 14.3 Hz, 1H), 1.20 (s, 18H) 216 088290.0189 31P NMR (162 MHz, CHLOROFORM-d) δ = -10.31 (s, 1P) TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.38 3. Preparation of compound 2：5 Two batches were carried out in parallel: To a solution of compound 2 (17.5 g, 57.89 mmol) in THF (400 mL) was added imidazole (10.25 g, 150.52 mmol), I2(23.51 g, 92.63 mmol, 18.66 mL) and PPh3 (24.30 g, 92.63 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS 10 showed compound 2 was consumed completely and one main peak with desired mass was detected. Two reactions were combined for work up. The reaction mixture was quenched by addition 10% Na2S2O3 aq.100 mL at 25 °C, and then concentrated under reduced pressure to remove THF, diluted with H2O (700 mL) and extracted with EtOAc (500 mL * 2). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered and 15 concentrated under reduced pressure to give a residue. The crude product was used directly for the next step without purification. Compound 2 (48 g, crude) was obtained as a yellow oil. LCMS: (M+H+): 412.9. 4. Preparation of compound 3： 20 For two batches: To a solution of compound 2 (22 g, 53.38 mmol) in DMF (250 mL) was added NaN3(3.09 g, 47.53 mmol) at 0 °C under N2. The mixture was stirred at 90 °C for 12 h. LCMS 217 088290.0189 showed compound 2 was consumed completely and desired mass was detected. The reaction was quenched by H2O (500 mL), and extracted with Ethyl acetate (500mL * 3). The combined organic dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 5 1: 0 to 0: 1). Compound 3 (34 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 11.40 (s, 1H), 7.70(d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.5 Hz, 1H), 5.68 (d, J = 7.8 Hz, 1H), 5.26 (d, J = 5.6 Hz, 1H), 4.10 - 4.02 (m, 2H), 3.92 (q, J = 4.8 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.66 - 3.57 (m, 3H), 3.47 - 3.42 (m, 2H), 3.25 - 3.20 (m, 3H) LCMS: (M+H+): 328.2 10 TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.34 5. Preparation of compound WV-NU-348： 15 To a solution of compound 3 (11.5 g, 35.14 mmol) and compound 5A (15.27 g, 45.68 mmol) in THF (50 mL) and H2O (50 mL) was added sodium ascorbate (8.35 g, 42.16 mmol) and CuSO4.5H2O (10.53 g, 42.16 mmol). The mixture was stirred at 65 °C for 6 h. LCMS showed compound 3 was consumed completely and desired mass was detected. The mixture was concentrated, the reaction mixture was extracted with EtOAc (50 mL * 3) and H2O 50 mL. 20 Then the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). Compound WV-NU-348 (10.7 g, 45.48% yield, 97.77% purity) was obtained as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ = 11.45 - 11.36 (m, 1H), 8.70 (s, 1H), 7.62 (d, J = 8.2 Hz, 25 1H), 5.80 (d, J = 4.6 Hz, 1H), 5.70 (s, 2H), 5.68 - 5.64 (m, 3H), 5.40 (d, J = 5.6 Hz, 1H), 4.85 - 4.71 (m, 2H), 4.21 - 4.17 (m, 1H), 4.14 - 4.08 (m, 2H), 3.75 - 3.67 (m, 1H), 3.67 - 3.59 (m, 1H), 3.46 (t, J = 4.8 Hz, 2H), 3.22 - 3.22 (m, 1H), 3.22 (s, 2H), 1.08 (s, 18H) 31PNMR (162 MHz, DMSO-d6) δ = 7.08 (s, 1P) 218 088290.0189 LCMS: (M+H+): 662.2, LCMS purity: 97.77% TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.32 EXAMPLE 1F. Synthesis of WV-NU-349 5 WV-NU-349 2'-LNA-5'-PO(POM)2-Triazolyl Phosphonate Uridine (WV-NU-349) (((1-(((1S,3R,4R,7S)-3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-7-hydroxy-2,5- dioxabicyclo[2.2.1]heptan-1-yl)methyl)-1H-1,2,3-triazol-4-10 yl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (WV-NU-349) General Scheme: 15 219 088290.0189 Experimental Procedure: 5 To a solution of compound 1C (36 g, 249.15 mmol) in THF (400 mL) was added bromo (ethynyl) magnesium (0.5 M, 498.29 mL) under N2. The mixture was stirred at 0 - 25 °C for 2 hr. TLC indicated compound 1C was consumed completely and one new spot formed. The each reaction mixture was quenched by addition NH4Cl 100mL at 0 °C. And then diluted with 10 water 300 mL and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10:1 to 0:1). Compound 2C (23 g, 17.21% yield) was obtained as a yellow oil 1H NMR (400 MHz, CHLOROFORM-d) δ = 3.82 (s, 3H), 3.79 (s, 3H), 2.97 (d, J =13.4 Hz, 15 1H) 31P NMR (162 MHz, CHLOROFORM-d) δ = -5.07 - -5.22 (m, 1P) TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.31 2. Preparation of compound 5A:20 For two batches: To a solution of compound 2C (11.5 g, 85.78 mmol) in ACN (500 mL) was added 4A MS (5 g, 85.78 mmol), iodomethyl 2,2-dimethylpropanoate (83.05 g, 343.10 mmol). The mixture was stirred at 82 °C for 15 hr. TLC indicated compound 2C was consumed 25 completely and two new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10:1 to 0:1). Compound 5A (33 g, 57.89% yield) was obtained as a colorless. 220 088290.0189 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.70 (d, J = 1.5 Hz, 2H), 5.66 (d, J = 0.8Hz, 2H), 3.06 (d, J = 14.3 Hz, 1H), 1.20 (s, 18H) 31P NMR (162 MHz, CHLOROFORM-d) δ = -10.31 (s, 1P) TLC: Petroleum ether: Ethyl acetate = 3:1, Rf = 0.38 5 3. Preparation of compound 2: For two batches: to a solution of compound 1 (50 g, 161.11 mmol) in DCM (800 mL) was 10 added pyridine (82.84 g, 1.05 mol) and the mixture was cooled to 0 °C, then MsCl (46.18 g, 403.14 mmol) was slowly added the mixture. The mixture was stirred at 0 - 20 °C for 12 hr. LCMS showed compound 1 was consumed completely and desired mass was detected. The mixture was cooled to 0 °C, the mixture of 100 mL ice water and aqueous NaHCO3100 mL was dropped to the mixture under N2, and stirred for 5 min. Then two batches with together, 15 the organic layer was separated and washed with saturated aqueous NaHCO3(300 ml*2) and with water. The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was used into the next step without further purification. Compound 2 (150 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.41 - 7.35 (m, 5H), 5.79 (d, J = 3.8 Hz, 1H), 20 4.88 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.68 - 4.63 (m, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 11.0 Hz, 1H), 4.22 - 4.12 (m, 2H), 3.08 (s, 3H), 2.98 (s, 3H), 1.68 (s, 3H), 1.34 (s, 3H) LCMS (M+Na+): 48925 4. Preparation of compound 3: 221 088290.0189 For three batches: to a solution of compound 2 (50 g, 107.18 mmol) was added TFA (250 mL) and H2O (62.5 mL). The mixture was stirred at 20 °C for 12 hr. LCMS showed compound 2 was consumed completely and desired mass was detected. Three batches with together. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was 5 diluted with NaHCO3 (500 mL) and extracted with DCM (300 mL * 2). The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 3 (137 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.64 (br d, J = 4.6 Hz, 1H), 7.48 – 7.45 (m, 10 1H), 7.41 - 7.30 (m, 5H), 5.39 - 5.34 (m, 1H), 4.66 - 4.59 (m, 2H), 4.35 -4.33 (m, 1H), 4.31 - 4.20 (m, 1H), 4.19 - 4.14 (m, 1H), 4.11 (d, J = 5.0 Hz, 1H), 3.05 - 2.97 (m, 6H) LCMS (M+Na+): 449.1 5. Preparation of compound 4: 15 For two batches: to a solution of compound 3 (65 g, 152.42 mmol) in PYRIDINE (600 mL) was added Ac2O (57.57 g, 563.95 mmol). The mixture was stirred at 20 °C for 12 hr. LCMS showed compound 3 was consumed completely and desired mass was detected. Two batches with together. The reaction mixture was diluted with NaHCO3(1000 mL) and extracted with 20 EtOAc (500 mL *2). The combined organic layers were washed with brine 800 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 0:1 to 1:1). Compound 4 (155 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.42 - 7.33 (m, 5H), 6.18 (s, 1H), 5.38 (d, J = 25 4.8 Hz, 1H), 4.65 - 4.60 (m, 1H), 4.55 - 4.48 (m, 2H), 4.43 (d, J = 4.8 Hz, 1H), 4.31 - 4.28 (m, 1H), 4.23 - 4.17 (m, 2H), 3.02 (d, J = 2.0 Hz, 6H), 2.16 (s, 3H), 2.11 (s, 3H) LCMS (M+Na+):533.1 TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.530 6. Preparation of compound 5:222 088290.0189 For three batches: to a solution of compound 4 (50 g, 97.94 mmol) and uracil (21.95 g, 195.87 mmol) in ACN (700 mL) was added BSA (69.73 g, 342.78 mmol) at 80 °C for 1 hr. Then 5 TMSOTf (54.42 g, 244.84 mmol) was added to the mixture. The mixture was stirred at 60 °C for 12 hr. LCMS showed compound 4 was consumed completely and desired mass was detected. The reaction mixture was cooled to 0 °C, and added to NaHCO3(800 mL). Three batches with together. The residue was extracted with EtOAc (500 mL * 3). The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentrated 10 under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 5 (78 g, 47.27% yield) and 78 g (crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.46 (br s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.39 - 7.29 (m,5H), 5.98 (d, J = 4.6 Hz, 1H), 5.68 (d, J = 8.0 Hz, 1H), 5.55 - 5.50 (m, 1H), 4.65 - 4.53 (m, 3H), 15 4.45 - 4.37 (m, 3H), 4.36 - 4.30 (m, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 2.05 (s, 3H) LCMS (M+Na+): 585.1, purity: 92.5% TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.5 7. Preparation of compound 6:20 For two batches: To a solution of compound 5 (41.5 g, 73.77 mmol) in dioxane (100 mL) and H2O (100 mL) was added NaOH (2 M, 221.31 mL). The mixture was stirred at 20 °C for 12 hr. LCMS showed compound 5 was consumed completely and one main peak with desired 25 mass was detected. Two batches with together. The reaction mixture was washed with 10% AcOH (300 mL). The residue was diluted with H2O (500 mL) and extracted with DCM (300 223 088290.0189 mL * 3). The combined organic layers were washed with NaHCO3(200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc at 20 °C for 5 min. The mixture was filtered and the cake was concentrated under reduced pressure to give product. Compound 6 (50 g, 79.85% 5 yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (br s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.37 - 7.25 (m, 5H), 5.60 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 4.83 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 3.0 Hz, 2H), 4.61 - 4.56 (m, 2H), 4.03 - 3.97 (m, 2H), 3.84 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H) LCMS (M+H+): 425.0, purity: 92.4% 10 TLC: Petroleum ether: Ethyl acetate = 0:1 Rf = 0.4 8. Preparation of compound 7: 15 To a solution of compound 6 (20 g, 47.12 mmol) in DMF (200 mL) was added NaN3(3.17 g, 48.76 mmol). The mixture was stirred at 60 °C for 12 hr. LCMS showed compound 6 was consumed completely and desired mass was detected. The reaction was quenched by H2O (100 mL), and extracted with Ethyl acetate (200 mL*3). The combined organic was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 20 was triturated with Petroleum ether: Ethyl acetate = 10:1, at 20 °C for 5 min. Then the mixture was filtered, the cake was washed with Petroleum ether, concentrated under reduced pressure to give product. Compound 7 (15.5 g, 88.58% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.37 - 7.27 (m, 5H), 5.65 (d, J = 8.2 Hz, 1H), 5.54 (s, 1H), 4.66 - 4.57 (m, 2H), 4.54 (s, 1H), 4.01 (d, J = 14.0 25 Hz, 1H), 3.94 - 3.89 (m, 2H), 3.87 - 3.77 (m, 2H) LCMS (M+H+): 372.0 9. Preparation of compound 8:224 088290.0189 To a solution of compound 7 (10 g, 26.93 mmol) and compound 5A (10.80 g, 32.31 mmol) in THF (100 mL) and H2O (100 mL) was added copper; sulfate; pentahydrate (8.07 g, 32.31 5 mmol) and sodium; (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (6.40 g, 32.31 mmol). The mixture was stirred at 65 °C for 6 hr. TLC indicated compound 7 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H2O (50 mL) and extracted with EtOAc (100 mL * 2). The combined organic layers were dried over Na2SO4, 10 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 8 (18 g, 94.72% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ =11.39 (s, 1H), 8.78 (s, 1H), 7.36 (d, J = 4.2 Hz, 4H), 7.33 - 7.26 (m, 2H), 5.73 (s, 2H), 5.69 (s, 2H), 5.52 (br d, J = 8.0 Hz, 1H), 5.47 (s, 1H), 5.28 (br d, 15 J = 15.0 Hz, 1H), 5.02 (br d, J = 15.0 Hz, 1H), 4.66 (s, 2H), 4.57 (s, 1H), 4.11 (d, J = 8.0 Hz, 1H), 3.58 (br d, J = 8.2 Hz, 2H), 1.10 (s, 18H) 31P NMR (162 MHz, DMSO-d6) δ = 6.73 (s, 1P) LCMS (M+H+): 706.3, purity: 94.7% TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.3 20 10. Preparation of WV-NU-349: 225 088290.0189 For two batches: to a solution of compound 8 (9 g, 12.75 mmol) in AcOH (100 mL) was added Pd / C (1.36 g, 1.28 mmol, 10% purity). The mixture was stirred at 30 °C for 12 hr under H2 (15 Psi). LCMS showed compound 8 was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a 5 residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1, Ethyl acetate: Methanol = 1:0 to 10:1). Compound WV-NU-349 (7.49 g, 49.93% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.38 (s, 1H), 8.78 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.11 (br d, J = 4.0 Hz, 1H), 5.72 (br d, J = 13.8 Hz, 3H), 5.51 (d, J = 8.0 Hz, 1H), 5.39 (s, 1H), 5.22 10 (d, J = 15.0 Hz, 1H), 4.96 (d, J = 15.0 Hz, 1H), 4.25 (s, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.86 (d, J = 3.6 Hz, 1H), 3.50 (d, J = 8.0 Hz, 1H), 1.11 (s, 18H) 31P NMR (162 MHz, DMSO-d6) δ = 6.75 (s, 1P) LCMS (M-H+): 616.2, purity: 98.88% TLC: Ethyl acetate: Methanol = 10:1, Rf = 0.3 15 EXAMPLE 1G. Synthesis of WV-NU-350 O,O-diethyl (1-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4- methoxytetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phosphonothioate (WV-NU-20 350). General Scheme: 226 088290.0189 5 Experimental Procedure: 1. Preparation of compound 2A : For three batches. To a solution of compound 1A (9.3 g, 59.41 mmol) in THF (100 mL) was 10 added bromo (ethynyl) magnesium (0.5 M, 120.00 mL) at 0 °C under N2. The resulting mixture was stirred at 0-15 °C for 2 hr. TLC indicated compound 1A was consumed completely and two new spots formed. The reaction was clean according to TLC. Three batches with together. The mixture was quenched by addition sat. NH4Cl (aq.150 mL) at 0 °C, then diluted with H2O (100 mL) and extracted with DCM (200 mL*3). The combined organic layers were dried over 15 Na2SO4, filtered to get the crude. Without purification. Compound 2A (26 g, crude) was obtained as a brown oil. TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.952. Preparation of compound 3A :227 088290.0189 For two batches. To a solution of compound 2A (13 g, 88.97 mmol) in DCM (150 mL) was added S (5.40 g, 168.41 mmol). The mixture was stirred at 15 °C for 2 hr. TLC indicated 5 compound 2A was consumed completely and one new spot formed. The reaction was clean according to TLC. Two batches with together. The reaction mixture was cooled to 0 °C and quenched by addition H2O 80 mL, and then diluted with H2O 50 mL and extracted with DCM 150 mL (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column 10 chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). Compound 3A (14 g, 44.16% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 4.16 (qd, J = 7.2, 10.3 Hz, 4H), 3.12 (d, J = 12.4 Hz, 1H), 1.34 (t, J = 7.2 Hz, 6H) 31P NMR (162 MHz, CHLOROFORM-d) δ = 51.30 (s, 1P) 15 LCMS (M+H+): 179.1 TLC: Petroleum ether: Ethyl acetate = 5:1, Rf = 0.7 3. Preparation of compound 2: 20 For five batches. To a solution of compound 1 (30 g, 116.18 mmol) in THF (420 mL) was added imidazole (20.56 g, 302.06 mmol), I2(47.18 g, 185.88 mmol) and PPh3(48.75 g, 185.88 mmol) at 0 °C. The mixture was stirred at 25 °C for 6 hr. TLC indicated compound 1 was consumed completely and two new spots formed. The reaction was clean according to TLC. 25 Five batches with together. The reaction was quenched by 10% aqueous sodium thiosulfate solution (800 ml). After removing the solvent and volatiles under reduced pressure, the residue was extracted into Dichloromethane (200 mL * 3) and washed with saturated aqueous NaHCO3 228 088290.0189 solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1 to Dichloromethane: Methanol = 1: 0 to 3: 1). The crude product was purified by re-crystallization from Ethyl acetate (100 mL), Dichloromethane (300 mL) and 5 Methanol (50 mL) at 15 °C. Compound 2 (200 g, 93.55% yield) was obtained as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.43 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 5.87 (d, J = 5.6 Hz, 1H), 5.70-5.68 (m, 1H), 5.46 (d, J = 6.0 Hz, 1H), 4.05-4.01 (m, 1H), 4.00-3.95 (m, 1H), 3.88-3.82 (m, 1H), 3.54-3.53 (m, 1H), 3.42-3.40 (m, 1H), 3.34 (s, 3H) LCMS (M+H+): 369.0 10 TLC: Dichloromethane: Methanol = 10:1, Rf = 0.45 4. Preparation of compound 3: 15 For five batches. To a solution of compound 2 (24 g, 65.20 mmol) in 1, 2-dimethoxyethane (300 mL) and H2O (60 mL) was added NaN3(3.66 g, 56.30 mmol) at 0 °C under N2. The mixture was stirred at 90 °C for 12 hr. LCMS showed compound 2 was remained and the desired mass was detected. Five batches with together. The reaction was quenched by H2O (500 mL), and extracted with Ethyl acetate (400 mL*3). The combined organic layers were 20 washed with saturated aqueous NaCl 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). The crude product was triturated with Ethyl acetate (50 mL) at 15 °C for 10 min. Compound 3 (49 g, 85.51% yield) was obtained as a white solid. 251H NMR (400 MHz, DMSO-d6) δ = 11.48 - 10.91 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H), 5.83 (d, J = 4.8 Hz, 1H), 5.68 (d, J = 8.0 Hz, 1H), 5.36 (br d, J = 5.8 Hz, 1H), 4.07 (q, J = 5.2 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.61 (d, J = 4.8 Hz, 2H), 3.36 (s, 3H) LCMS: (M+H+): 284.0, purity: 90.16%TLC: Dichloromethane: Methanol = 10:1, Rf = 0.45 229 088290.0189 5. Preparation of WV-NU-350: 5 To a solution of compound 3 (8 g, 28.24 mmol) and compound 3A (5.54 g, 31.07 mmol) in THF (80 mL) was degassed and purged with N2 for 3 times, then DIEA (7.30 g, 56.49 mmol), CuI (10.76 g, 56.49 mmol) was added. The mixture was stirred at 20 °C for 4 hr under N2 atmosphere. LCMS showed compound 3 was remained and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give product. The residue 10 was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). Compound WV-NU-350 (10 g, 76.92% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.41 (d, J = 1.6 Hz, 1H), 8.58 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 5.80 (d, J = 4.8 Hz, 1H), 5.64 - 5.62 (m, 1H), 5.49 (d, J = 6.2 Hz, 1H), 4.84 - 4.78 (m, 15 1H), 4.77 - 4.69 (m, 1H), 4.21 (td, J = 4.8, 7.8 Hz, 1H), 4.17 - 4.07 (m, 5H), 3.91 (t, J = 5.2 Hz, 1H), 3.36 (s, 3H), 1.24 (t, J = 7.0 Hz, 6H) 31P NMR (162 MHz, DMSO-d6) δ = 69.85 (s, 1P) LCMS (M+H+): 462.1, purity: 98.75% TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.25 20 EXAMPLE 1H. Synthesis of WV-NU-352 230 088290.0189 WV-NU-352 2'-OMe-5'-PO(OEt)2-Triazolyl methyl phosphonate Uridine (WV-NU-352)diethyl ((4-((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4- methoxytetrahydrofuran-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phosphonate (WV-NU-352) 5 General Scheme: 10 Experimental Procedure: 1. Preparation of compound 2:231 088290.0189 For two batches: To a solution of compound 1 (50 g, 193.63 mmol) in DMF (1000 mL) was added imidazole (52.73 g, 774.51 mmol) and TBSCl (87.55 g, 580.88 mmol). The mixture 5 was stirred at 20 °C for 12 hr. TLC indicated compound 1 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H2O 1500 mL and extracted with EtOAc 500 mL*3. The combined organic layers were washed with brine 1500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 2 (188 g, crude) was 10 obtained as a colorless oil. TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.7 2. Preparation of compound 3: 15 For four batches: To a solution of compound 2 (94 g, 193.12 mmol) in THF (1000 mL) at 0 °C under N2, and then added mixture of TFA (383.75 g, 3.37 mol) and H2O (250.00 g, 13.88 mol) slowly. The mixture was stirred at 0 °C for 3 hr. TLC indicated compound 2 was consumed completely and one new spot formed. The reaction mixture was quenched with NH3.H2O (230 20 mL *4) at 0 °C. Four batches with together. The residue was diluted with H2O 500 mL and extracted with DCM (1000 mL * 3). The combined organic layers were washed with brine 1000 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 3 (230 g, 79.93% yield) was obtained as a white solid. 232 088290.0189 1H NMR (400 MHz, DMSO-d6) δ = 11.36 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 5.83 (d, J = 5.0 Hz, 1H), 5.66 (d, J = 8.0 Hz, 1H), 5.21 (t, J = 5.0 Hz, 1H), 4.30 (t, J = 4.8 Hz, 1H), 3.87 - 3.81 (m, 2H), 3.70 - 3.61 (m, 1H), 3.55 – 3.51 (m, 1H), 3.34 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H) LCMS (M+H+): 373.1, purity: 100% 5 TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.6 3. Preparation of compound 4: 10 To a solution of compound 3 (25 g, 67.12 mmol) in DCM (500 mL) was added DMP (28.47 g, 67.12 mmol). The mixture was stirred at 0-25 °C for 3 hr. TLC indicated compound 3 was consumed completely and one new spot formed. The reaction mixture of three batches were diluted with NaHCO3500 mL and extracted with DCM 500 mL*3. The combined organic layers were washed with Sat. NaCl 100 mL, dried over Na2SO4, filtered and concentrated under 15 reduced pressure to get crude product. The crude product was used into the next step without further purification. Compound 4 (24 g, crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.59 - 11.25 (m, 1H), 7.92 - 7.89 (m, 1H), 5.94 (d, J = 7.7 Hz, 1H), 5.73 - 5.68 (m, 1H), 4.90 (d, J = 3.0 Hz, 1H), 4.46 (d, J = 4.6 Hz, 1H), 3.87 – 3.85 (m, 1H), 3.72 (d, J = 2.6 Hz, 1H), 3.61 - 3.58 (m, 3H), 0.90 - 0.88 (m, 9H), 0.10 (s, 6H) 20 TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.45 25 For two batches: to a solution of compound 4 (22 g, 59.38 mmol) and 1-diazo-1- dimethoxyphosphoryl-propan-2-one (11.41 g, 59.38 mmol) in MeOH (400 mL) was added 233 088290.0189 K2CO3(16.41 g, 118.77 mmol) at 0 °C under N2. The mixture was stirred at 0-20 °C for 12 hr. LCMS showed compound 4 was consumed completely and one main peak with desired mass was detected. Two batches with together. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O 300 mL and extracted 5 with DCM 200 mL * 3. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 5 (25 g, 57.44% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.43 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.4 10 Hz, 1H), 5.75 (d, J = 8.0 Hz, 1H), 4.49 - 4.46 (m, 1H), 4.44 (d, J = 4.6 Hz, 1H), 4.04 - 4.01 (m, 1H), 3.87 (d, J = 1.4 Hz, 1H), 3.36 (s, 3H), 0.89 (s, 9H), 0.13 (d, J = 3.2 Hz, 6H) LCMS (M-H+):367.1; purity: 95.3% TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.415 5. Preparation of compound 2A: To a solution of compound 1A (30 g, 107.90 mmol) in DMF (300 mL) was added NaN3(7.27 g, 111.83 mmol. The mixture was stirred at 90 °C for 12hr. TLC indicated compound 1A was 20 consumed completely and one new spot formed. The reaction was cooled to 0 °C, and quenched by H2O (300 mL), and extracted with Ethyl acetate (200 mL*3). The combined organic dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 2A (12 g, 57.58% yield) was obtained as a colorless oil. 251H NMR (400 MHz, DMSO-d6) δ = 4.25 - 4.14 (m, 4H), 3.46 (d, J = 11.8 Hz, 1H), 3.03 (d, J = 10.4 Hz, 1H), 1.39 - 1.32 (m, 6H) LCMS (M-H+):194.1 TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.2530 6. Preparation of compound 6 :234 088290.0189 To a solution of compound 5 (10 g, 27.29 mmol) and compound 2A (6.85 g, 35.47 mmol) in THF (50 mL) and H2O (50 mL) was added copper; sulfate; pentahydrate (8.18 g, 32.74 mmol) 5 and sodium; (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (6.49 g, 32.74 mmol). The mixture was stirred at 65 °C for 6 hr. TLC indicated compound 5 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H2O 100 mL and extracted with EtOAc (100 mL * 2). The combined organic layers were washed with brine 100 mL, 10 dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1). Compound 6 (9.7 g, 63.52% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (s, 1H), 8.21 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 5.90 (d, J = 3.4 Hz, 1H), 5.72 – 5.69 (m, 1H), 5.12 (br d, J = 13.0 Hz, 2H), 5.01 (d, J = 6.0 Hz, 1H), 15 4.60 - 4.54 (m, 1H), 4.12 - 4.03 (m, 5H), 3.43 (s, 3H), 1.24 - 1.18 (m, 6H), 0.80 (s, 9H), 0.00 (s, 3H), -0.11 (s, 3H) 31P NMR (162 MHz, DMSO-d6) δ = 17.19 (s, 1P) LCMS (M-H+):560.3; purity: 96.99% TLC: Petroleum ether: Ethyl acetate = 0:1, Rf = 0.3 20 7. Preparation of compound WV-NU-352: 235 088290.0189 To a solution of compound 6 (9 g, 16.08 mmol) in THF (95 mL) was added N,N- diethylethanamine; trihydrofluoride (10.37 g, 64.33 mmol). The mixture was stirred at 40 °C for 12 hr. TLC indicated compound 6 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove THF. The residue 5 was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 0:1, Ethyl acetate: Methanol = 1:0 to 5:1). Compound WV-NU-352 (4.3 g, 60.04% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.41 (br s, 1H), 8.18 (s, 1H), 7.89 – 7.87 (m, 1H), 5.96 (d, J = 3.8 Hz, 1H), 5.69 (d, J = 8.0 Hz, 1H), 5.54 -5.52 (m, 1H), 5.11 (br d, J = 13.0 Hz, 2H), 10 5.01 (d, J = 4.6 Hz, 1H), 4.40 (q, J = 5.0 Hz, 1H), 4.12 - 4.01 (m, 5H), 3.42 (d, J = 1.0 Hz, 3H), 1.21 (t, J = 7.0 Hz, 6H) 31P NMR (162 MHz, DMSO-d6) δ = 17.28 (s, 1P) LCMS (M-H+): 446.1; purity: 96.79% TLC: Ethyl acetate: Methanol = 8:1, Rf = 0.25 15 EXAMPLE 1I. Synthesis of WV-NU-362 20 General Scheme: 236 088290.0189 Preparation of diethyl (1-benzylpyrrolidin-3-yl)phosphonate (WV-NU-362-A) :5 To a stirred solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl) methenamine (12 g, 0.05063 mol) and diethyl vinylphosphonate (8.3 g, 0.05063) in dry ACN (120 mL, 10 vol), was added TFA (3.9 mL, 0.0563 mol) dropwise over a period for 10 min at 0oC. The resulting 10 mixture was stirred at rt for 6 h. Progress of the reaction was monitored by TLC. Then reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography over silica-gel (230-400 mesh) eluted in 40% acetone in hexane to get ayellow oil (WV-NU-362-A) (6 g, 40%), TLC Mobile phase details: 50% Acetone in Hexane.1H NMR (400 MHz, CDCl3): δ in ppm = 7.30 (m, 4H), 7.25 (m, 1H), 4.10 (m, 4H), 3.63 (s, 15 2H), 2.98 (m, 1H), 2.83 (m, 1H), 2.49 (m, 3H), 2.11 (m, 2H), 1.31 (t, 6H, J1 = 7.1 Hz). MS: m / z calcd for C15H24NO3P, 297.3; found 298.52, [M+H]+. 237 088290.0189 Preparation of diethyl pyrrolidin-3-ylphosphonate (WV-NU-362-B): To a stirred solution of (WV-NU-362-A) (6 g, 0.02289 mol) in dry MeOH (120 mL, 20 vol) 5 was added Ammonium formate (2.16 g, 0.03434 mol) and Pd / C (1.8 g, 30 mol %) portion wise at rt. The resulting mixture was stirred 40oC and kept for 1.5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the reaction mixture was filtered through celite bed, washed with MeOH (2 x 50 mL) and concentrated under reduced pressure to afford light yellow oil (WV-NU-362-B) (3.2 g, crude), TLC Mobile phase details: 10%10 MeOH in DCM.1H NMR (400 MHz, CDCl3): δ in ppm = 4.12 (m, 4H), 3.44 (s, 2H), 3.13 (m, 2H), 2.91 (m, 1H), 2.36 (m, 1H), 2.01 (m, 2H), 1.33 (t, 6H, J1 = 7.1 Hz. MS: m / z calcd for C8H18NO3P, 207.2; found 208.24 [M-H]+. Preparation of (2S,3S,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydro 15 pyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-2-carbaldehyde (WV-NU-362-02): To a stirred solution of (WV-NU-362-01) (5 g, 0.0134 mol) in dry DCM (125 mL, 25 vol) was20 added Dess-Martin Periodinane (7.4 g, 0.0174 mol) portion wise over a period of 20 min at 0oC. The reaction mixture was allowed to stir at rt for 2.5 h. Progress of the reaction was monitored by TLC. After completion, the reaction was quenched with a solution (1:1 ratio of Na2S2O3 : NaHCO3 (80 mL), extracted with DCM (2 x 60 mL), dried over Na2SO4 and concentrated under reduced pressure to afford off white solid (WV-NU-362-02) (4.6 g, crude),25 TLC Mobile phase details: 70% EtOAc in Hexane. 1H NMR (500 MHz, CDCl3): δ in ppm =9.78 (s, 1H), 8.58 (s, 1H), 7.63 (d, 1H, J1 = 7.6 Hz), 5.80 (t, 2H, J1 = 5.9 Hz), 4.54 (d, 1H, J1 238 088290.0189 = 4.1 Hz), 4.43 (t, 1H, J1 = 4.1 Hz), 3.93 (t, 1H, J1 = 4.8 Hz), 3.46 (m, 4H), 0.92 (m, 9H), 0.12 (m, 8H). MS: m / z calcd for C16H26N2O6Si, 370.05; found 371.32. [M-H]+. 5 Preparation of diethyl (1-(((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-4-methoxytetrahydrofuran-2- yl)methyl)pyrrolidin3yl)phosphonate (WV-NU-362-03): To a stirred solution of (WV-NU-362-B) (9 g, 0.0434 mol) in dry DCM (225 mL, 25 vol), 10 (WV-NU-362-02) (15 g, 0.04086 mol) at rt. was added Na (OAc)3BH (8.9 g, 0.06173 mol) portion wise over a period of 10 min, at 0oC. Then reaction mixture was stirred to 20oC for 8 h. Progress of the reaction was monitored by TLC. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) at 0oC and extracted with DCM (2 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford light yellow semi syrup. (WV-NU-362-03)15 (14.6 g, crude), TLC Mobile phase details: 10% MeOH in DCM.1H NMR (500 MHz, CDCl3):δ in ppm = 9.32 (s, 1H), 7.56 (dd, 1H, J1 = 45.4 Hz, J2 = 7.6 Hz), 5.81 (m, 1H), 5.72 (m, 1H), 4.11 (m, 6H), 3.96 (m, 1H), 3.64 (td, 1H, J1 = 5.9 Hz, J2 = 1.4 Hz), 3.51 (m, 3H), 3.38 (m, 1H), 3.00 (m, 2H), 2.79 (m, 2H), 2.55 (m, 3H), 2.05 (m, 2H), 1.31 (m, 7H), 0.91 (td, 11H, J1 = 6.7 Hz, J2 = 3.7 Hz), 0.79 (m, 6H). MS: m / z calcd for C24H44N3O8PSi, 561.7; found 362-59. 20 [M-H]+. Preparation of diethyl (1-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3- hydroxy-4-methoxytetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)phosphonate (WV-NU- 362): 25 239 088290.0189 To a stirred solution of (WV-NU-362-03) (14.6 g, 0.0260 mol) in H2O (73 mL, 5 vol), was added formic acid (73 mL, 5 vol) at 0oC. Then the reaction mixture was allowed to stir at rt for 24 h. Progress of the reaction was monitored by TLC. After completion, the reaction 5 mixture was concentrated under reduced pressure and the crude mass was codistilled with toluene (50 ml x3). The crude compound was purified by column chromatography over silica- gel (230-400 mesh) eluted in 6% MeOH in DCM to afford brown solid (WV-NU-362) (6.6 g, 56%), TLC Mobile phase details: 10% MeOH in DCM.1H NMR (500 MHz, D2O): δ in ppm =7.65 (d, 1H, J1 = 8.3 Hz), 5.87 (t, 2H, J1 = 3.4 Hz), 4.16 (m, 6H), 4.07 (q, 1H, J1 = 3.7 Hz),10 3.49 (s, 3H), 3.32 (m, 1H), 3.06 (m, 3H), 2.76 (m, 3H), 2.18 (d, 1H, J1 = 7.6 Hz), 2.06 (dt, 1H J1 = 14.0 Hz, J2 = 6.0 Hz), 1.31 (m, 6H). MS: m / z calcd for C18H30N3O8P, 447.4; found 449.7. [M-H]+. EXAMPLE 1J. Synthesis of WV-NU-343 15 Diethyl (1-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4- methoxytetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-5-yl)phosphonate (WV-NU-343) General Scheme: 20 240 088290.0189 Experimental Procedure: 1. Preparation of compound 2A：5 For three batches. To a solution of compound 1A (11 g, 70.27 mmol) in THF (150 mL) was added bromo (ethynyl) magnesium (0.5 M, 140.53 mL) at 0 °C under N2. The resulting mixture 10 was stirred at 15 °C for 2 hr. TLC indicated compound 1A was consumed completely and two new spots formed. The reaction was clean according to TLC. Three batches with together. The reaction mixture was quenched by sat. aq. NH4Cl (150 mL) at 0 °C, then extracted with DCM (100 mL*3). The combined organic layers were dried over Na2SO4, filtered to get the crude. Without purification. Compound 2A (1.87 g, crude) was obtained as a brown oil.15 TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.952. Preparation of compound 3A： 20 241 088290.0189 For two batches. To a solution of compound 2A (16 g, 109.50 mmol) in DCM (400 mL) was added m-CPBA (44.46 g, 218.99 mmol) at 0 °C. The mixture was stirred at 0-15 °C for 2 hr. TLC indicated compound 2A was consumed completely and two new spots formed. The reaction was clean according to TLC. Two batches with together. The reaction mixture was 5 quenched by sat. aq. Na2SO3 (300 mL) and NaHCO3 (300mL), then extracted with DCM (200 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). Compound 3A (35 g, 50.72% yield) was obtained as a yellow oil. 101H NMR (400 MHz, CHLOROFORM-d) δ = 4.17 (quin, J = 7.6 Hz, 4H), 2.92 (d, J = 13.4 Hz, 1H), 1.36 (t, J = 7.2 Hz, 6H) 31P NMR (162 MHz, CHLOROFORM-d) δ = -8.41 (s, 1P), -8.41 (s, 1P) TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.415 3. Preparation of compound 2： For five batches. To a solution of compound 1 (30 g, 116.18 mmol) in THF (420 mL) was added imidazole (20.56 g, 302.06 mmol), I2 (47.18 g, 185.88 mmol) and PPh3 (48.75 g, 185.88 20 mmol) at 0 °C. The mixture was stirred at 25 °C for 6 hr. TLC indicated compound 1 was consumed completely and two new spots formed. The reaction was clean according to TLC. Five batches with together. The reaction was quenched by 10% aqueous sodium thiosulfate solution (800 ml). After removing the solvent and volatiles under reduced pressure, the residue was extracted into Dichloromethane (200 mL * 3) and washed with saturated aqueous NaHCO325 solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1 to Dichloromethane: Methanol =1: 0 to 3: 1). The crude product was purified by re-crystallization from Ethyl acetate (100 mL), Dichloromethane (300 mL) and Methanol (50 mL) at 15 °C. Compound 2 (200 g, 93.55% yield) was obtained as a purple solid. 242 088290.0189 1H NMR (400 MHz, DMSO-d6) δ = 11.43 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 5.87 (d, J = 5.6 Hz, 1H), 5.70-5.68 (m, 1H), 5.46 (d, J = 6.0 Hz, 1H), 4.05-4.01 (m, 1H), 4.00-3.95 (m, 1H), 3.88-3.82 (m, 1H), 3.54-3.53 (m, 1H), 3.42-3.40 (m, 1H), 3.34 (s, 3H) LCMS (M+H+): 369.0 5 TLC: Dichloromethane: Methanol = 10:1, Rf = 0.45 4. Preparation of compound 3： 10 For five batches. To a solution of compound 2 (24 g, 65.20 mmol) in 1, 2-dimethoxyethane (300 mL) and H2O (60 mL) was added NaN3(3.66 g, 56.30 mmol) at 0 °C under N2. The mixture was stirred at 90 °C for 12 hr. LCMS showed compound 2 was remained and the desired mass was detected. Five batches with together. The reaction was quenched by H2O (500 mL), and extracted with Ethyl acetate (400 mL*3). The combined organic layers were 15 washed with saturated aqueous NaCl 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1). The crude product was triturated with Ethyl acetate (50 mL) at 15 °C for 10 min. Compound 3 (49 g, 85.51% yield) was obtained as a white solid. 201H NMR (400 MHz, DMSO-d6) δ = 11.48 - 10.91 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H), 5.83 (d, J = 4.8 Hz, 1H), 5.68 (d, J = 8.0 Hz, 1H), 5.36 (br d, J = 5.8 Hz, 1H), 4.07 (q, J = 5.2 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.61 (d, J = 4.8 Hz, 2H), 3.36 (s, 3H) LCMS: (M+H+): 284.0, purity: 90.16%TLC: Dichloromethane: Methanol = 10:1, Rf = 0.45 25 5. Preparation of WV-NU-343:243 088290.0189 For four batches. To a solution of compound 3 (10 g, 35.31 mmol) and compound 3A (11.45 g, 70.61 mmol) in Tol. (100 mL) was added chlororuthenium; cyclopentane; 5 triphenylphosphane (3.61 g, 4.94 mmol). The mixture was stirred at 90 °C for 12 hr. LCMS showed compound 3 was remained and the desired mass was detected. Four batches with together. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna c18 250mm*100mm*15um; mobile phase: [H2O (0.02%FA)-ACN]; gradient: 5%-25% B over 10 25.0 min). Compound WV-NU-343 (1.2 g, 1.91% yield) was obtained as a yellow solid. Compound WV-NU-306 (22 g, 34.98% yield) was obtained as a pale yellow solid. WV-NU-343: 1H NMR (400 MHz, DMSO-d6) δ = 11.42 (d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 7.68 (d, J = 8.0 15 Hz, 1H), 5.79 (d, J = 5.0 Hz, 1H), 5.66-5.64 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 4.89 (d, J = 6.0 Hz, 2H), 4.31 - 4.22 (m, 2H), 4.13 - 4.03 (m, 4H), 4.02 - 3.97 (m, 1H), 3.37 (s, 3H), 1.23 (q, J = 7.1 Hz, 6H) 31P NMR (162 MHz, DMSO-d6) δ = 3.10 (s, 1P) LCMS (M+H+): 446.1, purity: 97.53% 20 WV-NU-306: 1H NMR (400 MHz, DMSO-d6) δ = 11.41 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 5.80 (d, J = 4.8 Hz, 1H), 5.65-5.63 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 4.87 - 4.69 (m, 2H), 4.21 (td, J = 4.6, 7.8 Hz, 1H), 4.15 (q, J = 5.6 Hz, 1H), 4.12 - 4.03 (m, 4H), 3.93 (t, J = 5.0 Hz, 1H), 3.37 (s, 3H), 1.24 (t, J = 7.0 Hz, 6H) 2531P NMR (162 MHz, DMSO-d6) δ = 7.16 (s, 1P) LCMS (M+H+): 446.1, purity: 94.23% EXAMPLE 1K. Synthesis of WV-NU-342 244 088290.0189 General Scheme: 5 10 Experimental Procedures: 1. Preparation of compound 2A: Compound 1A (30 g, 217.23 mmol) was added to a stirred mixture of pyrrolidine-2-carboxylic 15 acid (37.51 g, 325.85 mmol) in Tol. (150 mL) at 110°C. Benzaldehyde (34.58 g, 325.85 mmol) was then added to the reaction mixture in small portions over 3 h. TLC indicated compound 245 088290.0189 1A was consumed completely and three new spots formed. The reaction was clean according to TLC. The resultant solution was portioned to H2O (500 mL), and extracted with EtOAc (2 X1000 mL). The organic layer was washed with brine (300 mL) and dried over Na2SO4. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (SiO2, 5 Petroleum ether / Ethyl acetate = 100:1 to 1:1). Compound 2A (55 g, 85.15% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, 25°C): δ = 7.16-7.30 (m, 5H), 5.22 (s, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.02-4.23 (m, 4H), 3.34 (d, J = 13.0 Hz, 1H), 2.91 (dd, J = 9.8, 5.8 Hz, 1H), 2.86 (ddd, J = 9.0, 6.5, 2.8 Hz, 1H), 2.16 (td, J = 9.4, 6.7 Hz, 1H), 1.97-2.10 (m, 2H), 10 1.61-1.77 (m, 2H), 1.27 ppm (td, J = 7.0, 4.6 Hz, 6H) 31P NMR (162 MHz, CHLOROFORM-d, 25°C): δ = 27.13 ppm (s, 1P) TLC: Petroleum ether: Ethyl acetate = 1: 1; Rf = 0.5 15 For two batches: To a solution of compound 2A (25 g, 84.08 mmol), AcOH (7.57 g, 126.12 mmol) in EtOH (250 mL) was added Pd (OH)2 (2.5 g, 20% purity) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H220 (15 Psi) at 25 °C for 12 hr. TLC indicated compound 2A was consumed completely and one new spot formed. The reaction was clean according to TLC. Filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100:1 to 13:1). Compound 3A (31 g, 88.97% yield) was obtained as a yellow oil. 25 1H NMR (400 MHz, CHLOROFORM-d, 25°C): δ = 4.04-4.16 (m, 4H), 3.33 (td, J = 8.0, 6.3 Hz, 1H), 2.96-3.05 (m, 1H), 2.85-2.96 (m, 1H), 1.97-2.06 (m, 1H), 1.77-1.94 (m, 2H), 1.66- 1.76 (m, 1H), 1.27 ppm (t, J = 7.0 Hz, 6H) TLC: Dichloromethane: Methanol = 10:1, Rf = 0.1530 3. Preparation of compound 2:246 088290.0189 To a solution of compound 1 (50 g, 193.63 mmol) in DMF (500 mL) was added imidazole (65.91 g, 968.14 mmol) and TBSCl (116.73 g, 774.51 mmol). The mixture was stirred at 25 5 °C for 3hr. TLC indicated compound 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between Ethyl acetate (3L) and H2O (1L). The organic phase was separated, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100:1 10 to 0:1). Compound 2 (94 g, 99.74% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, 25°C): δ = 8.63 (br s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 5.83 (d, J = 1.6 Hz, 1H), 5.57 (dd, J = 8.0, 2.0 Hz, 1H), 4.13 (dd, J = 7.0, 4.9 Hz, 1H), 3.91-3.97 (m, 2H), 3.63-3.70 (m, 1H), 3.50 (dd, J = 4.8, 1.7 Hz, 1H), 3.45 (s, 3H), 0.82 (d, J = 13.0 Hz, 18H), -0.04-0.03 ppm (m, 12H) 15 LCMS: (M+H+) = 487.4 TLC: Petroleum ether: Ethyl acetate = 1:1, Rf = 0.48 4. Preparation of compound 3: 20 For 2 batches: To a solution of compound 2 (60 g, 123.27 mmol) in H2O (300 mL) / TFA (300 mL) / THF (600 mL). The mixture was stirred at 0 °C for 3hr. TLC indicated compound 2 was consumed completely and one new spot formed. The reaction was clean according to TLC. 2 reactions were combined for workup. After completion of reaction, the resulting mixture was 25 added con.NH3*H2O (1L) to pH = 7, and then extracted with ethyl acetate (2 L) washed with 247 088290.0189 brine 500 mL dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100:1 to 0;1). Compound 3 (60 g, 65.34% yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d, 25°C): δ = 9.38 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 5 5.67-5.76 (m, 2H), 4.36 (t, J = 5.4 Hz, 1H), 3.94-4.08 (m, 3H), 3.75 (br d, J = 12.2 Hz, 1H), 3.49 (s, 3H), 2.87 (br s, 1H), 0.92 (s, 9H), 0.11 ppm (d, J = 5.0 Hz, 6H) TLC: Petroleum ether: Ethyl acetate = 1:2, Rf = 0.28 5. Preparation of compound 4:10 DMP (22.77 g, 53.69 mmol) was added to a stirred and cooled 0 °C solution of compound 3 (20 g, 53.69 mmol) in anhydrous DCM (300 mL) under argon atmosphere. The cooling bath was removed, and the mixture was stirred at 25°C for 3hr. TLC indicated compound 3 was consumed completely and one new spot formed. The reaction was clean according to TLC. 15 The mixture was cooled to 0 °C and poured to a vigorously stirred mixture of 10% solution of sodium thiosulfate (100 mL) and saturated solution of sodium bicarbonate (100 mL). After stirring at room temperature for 45 minutes significant precipitation occurred. The precipitate was filtered off and the solids where washed with DCM (200 mL x 2). The filtrate was placed in a separator funnel, the organic phase was separated and dried over anhydrous sodium sulfate. 20 Without further purification. Compound 4 (19 g, crude) was obtained as a white solid. TLC: (Petroleum ether: Ethyl acetate = 0:1), Rf = 0.58 6. Preparation of compound 5: 25 248 088290.0189 To a solution of compound 3A (15.94 g, 76.93 mmol) compound 4 (19...

Claims

088290.0189 CLAIMS What is claimed is:

1. A double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)- 5 specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein: a) the guide strand comprises at least 15 contiguous nucleotides differing by: i. no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAG GAUU-3’; 10 ii. no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAG GAUU-3’; iii. no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGA AGGA-3’; or iv. no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAAGGA-3’; 15 b) the guide strand comprises: i) a non-negatively charged internucleotidic linkage in the Sp configuration between the +3 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+4) nucleotide; ii) a non-negatively charged internucleotidic linkage in the Rp configuration 20 between the +10 nucleotide, relative to the 5’ terminal nucleotide, and the immediately downstream (+11) nucleotide; iii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal nucleotide (N) and the penultimate (N-1) nucleotide; iv) a phosphorothioate internucleotidic linkage in the Sp configuration between 25 the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide; and v) a 5’ phosphate modification at the 5’ terminal nucleotide; c) the passenger strand comprises: i) a phosphorothioate internucleotidic linkage in the Sp configuration between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide; and 30 ii) a phosphorothioate internucleotidic linkage in the Sp configuration between the 3’ terminal (N) nucleotide and the penultimate (N-1) nucleotide; d) the guide strand and the passenger strand each independently has a length of 15-49 nucleotides; and 341088290.0189 e) the dsRNAi agent comprises a carbohydrate moiety connected at a nucleoside or an internucleotidic linkage.

2. The dsRNAi agent of claim 1, wherein the 5’ phosphate modification at the 5’ terminal 5 nucleotide is selected from: , , 10342088290.0189, wherein: the base is selected from A, C, G, T, U, abasic, and modified nucleobases; R1is selected from H, OH, O-alkyl, O-methyl (O-Me), F, O-methoxyethyl (MOE), and 2’- O,4’C-methylene-bridged or locked nucleic acid (2’,4’-BNA or LNA); and 5 R2is selected from alkyl, methyl, ethyl, isopropyl, propyl, cyclohexyl, benzyl, phenyl, tolyl, xylyl, aryl, and arene group.

3. The dsRNAi agent of claim 2, wherein the 5’ phosphate modification at the 5’ terminal nucleotide i. 10 4. The dsRNAi agent of any of the preceding claims, wherein the guide strand comprises one or more non-negatively charged internucleotidic linkages in the Rp or the Sp configuration between: a. the +4 nucleotide, relative to the 5’ terminal nucleotide, and the +10 nucleotide, 15 relative to the 5’ terminal nucleotide; b. the +11 nucleotide, relative to the 5’ terminal nucleotide, and the N-2 nucleotide, relative to the 3’ terminal nucleotide; or c. combinations thereof. 20 5. The dsRNAi agent of any of the preceding claims, wherein the guide strand comprises at least one 2’ sugar moiety modification.

6. The dsRNAi agent of claim 4, wherein said 2’ sugar moiety modification is a 2’- methoxy (2’-OMe) sugar moiety modification. 25 7. The dsRNAi agent of claim 4, wherein said 2’ sugar moiety modification is a 2’- fluoro (2’-F) sugar moiety modification. 343088290.0189 8. The dsRNAi agent of claims 5 to 7, wherein the guide strand comprises a 2’ sugar moiety modification of the 3’ nucleotide of a nucleotide pair linked by a non-negatively charged internucleotidic linkage. 5 9. The dsRNAi agent of claim 8, wherein said 2’ sugar moiety modification is a 2’- fluoro (2’-F) sugar moiety modification.

10. The dsRNAi agent of claim 6, wherein the guide strand comprises seven contiguous 10 2’-OMe sugar moiety modifications.

11. The dsRNAi agent of claim 10, wherein the guide strand comprises seven contiguous 2’-OMe sugar moiety modifications at the +17 to +23 nucleotides, relative to the 5’ terminal nucleotide. 15 12. The dsRNAi agent of claim 7, wherein the guide strand comprises six 2’-F sugar moiety modifications.

13. The dsRNAi agent of claim 12, wherein the guide strand comprises six 2’-F sugar 20 moiety modifications at the +2, +4, +6, +11, +14, and +16 nucleotides, relative to the 5’ terminal nucleotide.

14. The dsRNAi agent of claim 6, wherein the guide strand comprises: a. four 2’-OMe sugar moiety modifications at the +7 to +10 nucleotides, relative to25 the 5’terminal nucleotide; b. a 2’-OMe sugar moiety modification at the +3 nucleotide, relative to the 5’ terminalnucleotide; c. two 2’-OMe sugar moiety modifications at the +12 and +13 nucleotides, relative tothe 5’ terminal nucleotide;30 d. a 2’-OMe sugar moiety modification at the +15 nucleotide, relative to the 5’terminal nucleotide; or e. combinations thereof.344088290.0189 15. The dsRNAi agent of claims 5 to 14, wherein the guide strand comprises a 2’ sugar moiety modification pattern of: 5’-m[fl2r]m[fl2r]m[fl2r]mmmm[fl2r]mm[fl2r]m[fl2r]mmmmmmm -3’ wherein: 5 m represents a 2’-OMe sugar moiety modification; and [fl2r] represents a 2’-F sugar moiety modification.

16. The dsRNAi agent of claim 15, wherein the guide strand comprises an internucleotidic linkage modification pattern of: 10 5’-mPS[fl2r]PSmPN[fl2r]POmPO[fl2r]POmPOmPOmPOmPN[fl2r]POmPOmPO [fl2r]POmPO[fl2r]POmPOmPOmPOmPOmPSmPSm-3’ wherein: PS represents a phosphorothioate internucleotidic linkage; PN represents a phosphoryl guanidine internucleotidic linkage; and 15 PO represents a phosphodiester or phosphate internucleotidic linkage.

17. The dsRNAi agent of claim 16, wherein the phosphorothioate internucleotidic linkage between the 5’ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide of the guide strand is in the Sp configuration. 20 18. The dsRNAi agent of claim 16, wherein the phosphorothioate internucleotidic linkage between the +2 nucleotide and the immediately downstream (+3) nucleotide of the guide strand is in the Rp configuration. 25 19. The dsRNAi agent of any of the preceding claims, wherein the passenger strand comprises at least one 2’ sugar moiety modification.

20. The dsRNAi agent of claim 19, wherein said 2’ sugar moiety modification is a 2’- methoxy (2’-OMe) sugar moiety modification. 30 21. The dsRNAi agent of claim 19, wherein said 2’ sugar moiety modification is a 2’- fluoro (2’-F) sugar moiety modification. 345088290.0189 22. The dsRNAi agent of claim 20-21, wherein the passenger strand comprises three contiguous 2’-F sugar moiety modifications and 10 contiguous 2’-OMe sugar moiety modifications. 5 23. The dsRNAi agent of claims 19 and 22-23, wherein the passenger strand comprises four 2’-F sugar moiety modifications.

24. The dsRNAi agent of claim 23, wherein the passenger strand comprises four 2’-F sugar moiety modifications at the +7, +9, +10, and +11 nucleotides, relative to the 5’ terminal 10 nucleotide.

25. The dsRNAi agent of claim 20, wherein the passenger strand comprises: a. six 2’-OMe sugar moiety modifications at the +1 to +6 nucleotides, relative to the5’ terminal nucleotide;15 b. one 2’-OMe sugar moiety modification at the +8 nucleotide, relative to the 5’terminal nucleotide; c. ten 2’-OMe sugar moiety modifications a the +12 to +21 nucleotides, relative to the5’ terminal nucleotide; or d. combinations thereof.20 26. The dsRNAi agent of claims 19-25, wherein the passenger strand comprises a 2’ sugar moiety modification pattern of: 5’-mmmmmm[fl2r]m[fl2r][fl2r][fl2r]mmmmmmmmmm-3’ wherein: 25 m represents a 2’-OMe internucleotidic linkage; and [fl2r] represents a 2’-F internucleotidic linkage.

27. The dsRNAi agent of claim 26, wherein the passenger strand comprises an internucleotidic linkage modification pattern of: 30 5’-mPSmPOmPOmPOmPOmPO[fl2r]POmPO[fl2r]PO[fl2r]PO[fl2r]POmPO mPOmPOmPOmPOmPOmPOmPOmPSm-3’ wherein: PS represents a phosphorothioate internucleotidic linkage; and PO represents a phosphodiester or phosphate internucleotidic linkage. 346088290.0189 28. The dsRNAi agent of claim 27, wherein each phosphorothioate internucleotidic linkage is independently in the Sp configuration. 5 29. The dsRNAi agent of any of the preceding claims, wherein the non-negatively charged internucleotidic linkage has a neutral charge.

30. The dsRNAi agent of claim 29, wherein the non-negatively charged internucleotidic linkage iare each independently 0-49.10 31. The dsRNAi agent of any of claim 30, wherein the non-negatively charged internucleotidic linkage i.

32. The dsRNAi agent of any of the preceding claims, wherein the carbohydrate moiety is 15 a mono-GalNAc, a bis-GalNAc, a tri-GalNAc, a mannose derivative, a galactose derivative, a glucose sugar derivative, other saccharide derivatives or combinations thereof.

33. The dsRNAi agent of claim 32, wherein the carbohydrate moiety is a tri-GalNAc (GalNAc3). 20 34. The dsRNAi agent of any of the preceding claims, wherein the carbohydrate moiety is connected at a nucleoside or an internucleotidic linkage through a linker.

35. The dsRNAi agent of claim 34, wherein the linker is C12oyl, and wherein a GalNAc3 25 linked to C12oyl (GalNAc3C12oyl) is 347088290.0189.

36. The dsRNAi agent of any of the preceding claims, wherein the carbohydrate moiety is connected at the 5’ end of the passenger strand. 5 37. The dsRNAi agent of any of the preceding claims, wherein the guide strand and the passenger strand each independently have a length of 20-25 nucleotides.

38. A double-stranded RNAi (dsRNAi) agent capable of directing INHBE (inhibin βE)- 10 specific RNA interference, the dsRNAi agent comprising a guide strand and a passenger strand, wherein: a) the guide strand comprises at least 15 contiguous nucleotides differing by: i. no more than 4 nucleotides from 5’-UAAGACGGCAGAAUGGAAG GAUU-3’; 15 ii. no more than 3 nucleotides from 5’-AAGACGGCAGAAUGGAAG GAUU-3’; iii. no more than 2 nucleotides from 5’-UAAGACGGCAGAAUGGA AGGA-3’; or iv. no more than 1 nucleotide from 5’-AAGACGGCAGAAUGGAA 20 GGA-3’; b) the guide strand comprises 2’ sugar moiety and internucleotidic modification patterns of: 5’-mPS[fl2r]PSmPN[fl2r]POmPO[fl2r]POmPOmPOmPOmPN[fl2r]POmPOmPO [fl2r]POmPO[fl2r]POmPOmPOmPOmPOmPSmPSm-3’; and 25 the passenger strand comprises 2’ sugar moiety and internucleotidic modification patterns of: 348088290.0189 5’-mPSmPOmPOmPOmPOmPO[fl2r]POmPO[fl2r]PO[fl2r]PO[fl2r]POmPO mPOmPOmPOmPOmPOmPOmPOmPSm-3’; wherein: PS represents a phosphorothioate internucleotidic linkage; 5 PN represents a phosphoryl guanidine internucleotidic linkage; and PO represents a phosphodiester or phosphate internucleotidic linkage; c) the guide strand comprises a 5’ phosphate modification at the 5’ terminal nucleotide thereof, wherein the 5’ phosphate modificationd) the passenger strand comprises a carbohydrate moiety, wherein the 10 carbohydrate moiety is a tri-GalNAc (GalNAc3) at the 5’-end of the passenger strand.

39. The dsRNAi agent of claim 38, wherein the guide strand comprises one or more of: a. a phosphorothioate internucleotidic linkage between the +1 and +2 nucleotides,relative to the 5’ terminal nucleotide, in the Sp configuration,15 b. a phosphorothioate internucleotidic linkage between the +2 and +3 nucleotides,relative to the 5’ terminal nucleotide, in the Rp configuration, c. a phosphoryl guanidine internucleotidic linkage between the +3 and +4 nucleotides,relative to the 5’ terminal nucleotide, in the Sp configuration, and d. a phosphoryl guanidine internucleotidic linkage between the +10 and +1120 nucleotides, relative to the 5’ terminal nucleotide, in the Rp configuration.

40. The dsRNAi agent of claim 38, wherein the passenger strand comprises phosphorothioate internucleotidic linkages between the +1 and +2 nucleotide, relative to the 5’ terminal nucleotide, in the Sp configuration, and between the N and N-1 nucleotides, 25 relative to the 3’ terminal nucleotide, in the Sp configuration.

41. The dsRNAi agent of claim 38, the carbohydrate moiety is connected at the 5’ end of the passenger strand through a C12oyl linker and wherein a GalNAc3 linked to C12oyl (GalNAc3C12oyl) is 349088290.0189.

42. The dsRNAi agent of any of claim 38, wherein the phosphoryl guanidine internucleotidic5 43. A composition comprising the dsRNAi agent of any of the preceding claims and a second agent, wherein the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; 10 a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; 15 and combinations thereof.

44. A method for preventing or treating an INHBE-related disorder in a subject in need thereof, comprising administering to the subject the dsRNAi agent of any of claims 1-42. 20 45. The method of claim 44, wherein said prevention or treatment of an INHBE-related disorder is selected from: improving glucose control; increasing lean body mass; reducing fat mass; treating obesity, e.g., abdominal obesity; treating diabetes, e.g., type 2 diabetes; treating insulin resistance; coronary artery disease; treating chronic kidney disease; treating liver issues associated with increased fat mass, obesity, and / or diabetes; treating a metabolic 350088290.0189 disorder; treating an elevated triglyceride level; treating a lipodystrophy; treating liver inflammation; treating fatty liver disease; treating hypercholesterolemia; treating an elevated liver enzyme; treating nonalcoholic steatohepatitis (NASH); treating a cardiovascular disease; treating cardiomyopathy; treating high blood pressure; treating heart failure; and inducing 5 lipolysis (fat-burning) while preserving muscle mass.

46. The method of either claim 44 or 45, comprising administering to the subject the dsRNAi agent prior to, concurrently with, and / or after: performing bariatric surgery on the subject; and / or 10 administering a second agent to the subject, where the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin- 4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; 15 sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof. 20 47. The method of claim 46, wherein the second agent is a GLP-1 receptor agonist (GLP- 1 agonist).

48. The method of claim 47, wherein the GLP-1 agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, tirzepatide, and semaglutide. 25 49. The method of claim 48, wherein the GLP-1 agonist is semaglutide.

50. The method of any of claims 43-49, wherein the dsRNAi agent and the second agent are administered to the subject concurrently. 30 51. The method of any of claims 43-50, wherein the dsRNAi agent and the second agent are administered to the subject sequentially. 351088290.0189 52. The method of claim 51, wherein the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent continues upon said administration of the dsRNAi agent is administered to the subject. 5 53. The method of claim 51, wherein the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent terminates upon said administration of the dsRNAi agent is administered to the subject.

54. The method of any of claims 46-53, wherein the second agent is administered to the 10 subject daily.

55. The method of any of claims 46-54, wherein the amount of the second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent. 15 56. The method of claim 46, wherein said bariatric surgery is performed on the subject before the dsRNAi agent is administered to the subject.

57. The method of any of claims 46-56, wherein the dsRNAi agent is administered every20 six months after the subject has been administered the second agent or has undergone said bariatric surgery.

58. The method of any of claims 46-56, wherein the dsRNAi agent is administered annually after the subject has been administered the second agent or has undergone said 25 bariatric surgery.

59. The method of any of claims 46-58, wherein the subject loses substantially more body weight compared to when the subject is administered the second agent alone. 30 60. The method of claim 59, wherein the subject loses about double the body weight compared to when the subject is administered the second agent alone.

61. The method of any of claims 46-60, wherein the subject does not undergo rebound body weight gain which is expected when the subject is administered the second agent alone. 352088290.0189 62. The method of any of claims 43-44, wherein the dsRNAi agent is administered everysix months. 5 63. The method of any of claims 43-44, wherein the dsRNAi agent is administered annually.

64. The method of any of claims 43-63, wherein the dsRNAi agent is administered subcutaneously. 10 65. The method of any of claims 43-64, wherein the subject maintains at least 50%, 60%, 75%, 90%, or 95% of its pre-administration skeletal muscle mass.

66. The method of any of claims 43-65, wherein the subject loses the body weight 15 without loss of muscle mass or without substantial loss of muscle mass.

67. The method of claim 66, wherein said loss of the body weight is accompanied by a reduction in fat mass. 20 68. The method of claim 67, wherein said reduction in fat mass is a reduction in visceral fat mass.

69. The method of any of claims 66-68, wherein said effects on the subject’s muscle mass and fat mass are consistent with the protective effects of heterozygous INHBE loss-of- 25 function (LoF) mutations.

70. The method of any of claims 43-69, wherein a healthy metabolic profile of the subject is maintained. 30 71. The method of any of claim 43-70, wherein the subject is administered the second agent (e.g., GLP-1 agonist) in a dosage amount that is the same as or lower than a standard dosage amount. 353088290.0189 72. The method of any of claims 43-71, wherein infiltration of activated macrophages in visceral adipose is decreased.

73. The method of claim 72, wherein infiltration of activated macrophages in visceral 5 adipose is decreased by at least 50%.

74. The method of claim 72 or 73, wherein said decreased infiltration of activated macrophages in visceral adipose is associated with treating type 2 diabetes and / or coronary artery disease. 10 75. The method of claim 74, wherein said type 2 diabetes and / or coronary artery disease is / are secondary to obesity.

76. The dsRNAi agent of any one of claims 1-42 for use in preventing or treating an 15 INHBE-related disorder in a subject in need thereof.

77. The dsRNAi agent for the use of claim 76, further comprising administering a second agent, wherein the second agent is selected from: a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist;20 an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon- like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; 25 an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof.

78. The dsRNAi agent for the use of either claim 76 or claim 77, wherein said prevention or treatment of an INHBE-related disorder is selected from: improving glucose control; increasing lean body mass; reducing fat mass; treating obesity, e.g., abdominal obesity; 30 treating diabetes, e.g., type 2 diabetes; treating insulin resistance; coronary artery disease; treating chronic kidney disease; treating liver issues associated with increased fat mass, obesity, and / or diabetes; treating a metabolic disorder; treating an elevated triglyceride level; treating a lipodystrophy; treating liver inflammation; treating fatty liver disease; treating 354088290.0189 hypercholesterolemia; treating an elevated liver enzyme; treating nonalcoholic steatohepatitis (NASH); treating a cardiovascular disease; treating cardiomyopathy; treating high blood pressure; treating heart failure; and inducing lipolysis (fat-burning) while preserving muscle mass. 5 79. The dsRNAi agent for the use of any of claims 76-78, comprising administering to the subject the dsRNAi agent prior to, concurrently with, and / or after: performing bariatric surgery on the subject; and / or administering a second agent to the subject, where the second agent is selected from: 10 a gastric and / or pancreatic lipase inhibitor; a norepinephrine agonist, a gamma-aminobutyric acid agonist, and / or a glutamate antagonist; an opioid receptor antagonist, a dopamine and norepinephrine reuptake inhibitor; a glucagon-like peptide 1 (GLP-1) agonist; an melanocortin-4 receptor (MC4R) agonist; a gastric inhibitory polypeptide (GIP) / GLP-1 dual agonist; insulin; sulfonylurea; meglitinide; biguanide; thiazolidinedione; an alpha-glucosidase 15 inhibitor; a SGLT2 inhibitor; a DPP4 inhibitor; a HMG-CoA reductase inhibitor, statins; a PCSK9 inhibitor; an ApoC3 inhibitor; an ANGPTL3 inhibitor; an ATP citrate lyase; ezetimide; an Lp(a) inhibitor; an LPL activator; and combinations thereof.

80. The dsRNAi agent for the use of claim 79, wherein the second agent is a GLP-1 20 receptor agonist (GLP-1 agonist).

81. The dsRNAi agent for the use of claim 80, wherein the GLP-1 agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, tirzepatide, and semaglutide. 25 82. The dsRNAi agent for the use of claim 81, wherein the GLP-1 agonist is semaglutide.

83. The dsRNAi agent for the use of any of claims 76-82, wherein the dsRNAi agent and the second agent of any of claims 80-82 (the second agent) are administered to the subject concurrently. 30 84. The dsRNAi agent for the use of any of claims 76-83, wherein the dsRNAi agent and the second agent are administered to the subject sequentially. 355088290.0189 85. The dsRNAi agent for the use of claim 84, wherein the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent continues upon said administration of the dsRNAi agent is administered to the subject. 5 86. The dsRNAi agent for the use of claim 84, wherein the second agent is administered before the dsRNAi agent is administered to the subject, and wherein said administration of the second agent terminates upon said administration of the dsRNAi agent is administered to the subject. 10 87. The dsRNAi agent for the use of any of claims 79-86, wherein the second agent is administered to the subject daily.

88. The dsRNAi agent for the use of any of claims 79-87, wherein the amount of the 15 second agent administered to the subject is reduced relative to a reference dose of the second agent administered in the absence of the dsRNAi agent.

89. The dsRNAi agent for the use of claim 79, wherein said bariatric surgery is performed on the subject before the dsRNAi agent is administered to the subject. 20 90. The dsRNAi agent for the use of any of claims 79-89, wherein the dsRNAi agent isadministered every six months after the subject has been administered the second agent or has undergone said bariatric surgery. 25 91. The dsRNAi agent for the use of any of claims 79-89, wherein the dsRNAi agent is administered annually after the subject has been administered the second agent or has undergone said bariatric surgery.

92. The dsRNAi agent for the use of any of claims 79-91, wherein the subject loses 30 substantially more body weight compared to when the subject is administered the second agent alone.

93. The dsRNAi agent for the use of claim 92, wherein the subject loses about double the body weight compared to when the subject is administered the second agent alone. 356088290.0189 94. The dsRNAi agent for the use of any of claims 79-93, wherein the subject does not undergo rebound body weight gain which is expected when the subject is administered the second agent alone. 5 95. The dsRNAi agent for the use of any of claims 76-77, wherein the dsRNAi agent isadministered every six months.

96. The dsRNAi agent for the use of any of claims 76-77, wherein the dsRNAi agent is 10 administered annually.

97. The dsRNAi agent for the use of any of claims 76-96, wherein the dsRNAi agent is administered subcutaneously. 15 98. The dsRNAi agent for the use of any of claims 76-97, wherein the subject maintains at least 50%, 60%, 75%, 90%, or 95% of its pre-administration skeletal muscle mass.

99. The dsRNAi agent for the use of any of claims 76-98, wherein the subject loses the body weight without loss of muscle mass or without substantial loss of muscle mass. 20 100. The dsRNAi agent for the use of claim 99, wherein said loss of the body weight is accompanied by a reduction in fat mass.

101. The dsRNAi agent for the use of claim 100, wherein said reduction in fat mass is a 25 reduction in visceral fat mass.

102. The dsRNAi agent for the use of any of claims 99-100, wherein said effects on the subject’s muscle mass and fat mass are consistent with the protective effects of heterozygous INHBE loss-of-function (LoF) mutations. 30 103. The dsRNAi agent for the use of any of claims 76-102, wherein a healthy metabolic profile of the subject is maintained. 357088290.0189 104. The dsRNAi agent for the use of any of claims 76-103, wherein the subject is administered the second agent (e.g., GLP-1 agonist) in a dosage amount that is the same as or lower than a standard dosage amount. 5 105. The dsRNAi agent for the use of any of claims 76-104, wherein infiltration of activated macrophages in visceral adipose is decreased.

106. The dsRNAi agent for the use of claim 105, wherein infiltration of activated macrophages in visceral adipose is decreased by at least 50%. 10 107. The dsRNAi agent for the use of claim 105 or 106, wherein said decreased infiltration of activated macrophages in visceral adipose is associated with treating type 2 diabetes and / or coronary artery disease. 15 108. The dsRNAi agent for the use of claim 107, wherein said type 2 diabetes and / or coronary artery disease is / are secondary to obesity. 20 358

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