Oligonucleotides for the treatment of angiopoietin-like 4 (ANGPTL4)-related diseases

Abstract

Compositions are provided, comprising oligonucleotides targeting angiopoietin-like 4 (ANGPTL4). The oligonucleotides may include small interfering RNA (siRNA) or antisense oligonucleotides (ASO). Also provided herein are methods of treating metabolic or cardiovascular disorders by providing an oligonucleotide targeting ANGPTL4 to a subject in need thereof.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 945,732, filed December 9, 2019, which is incorporated herein by reference in its entirety.

[0003] Incorporation by Reference into the Sequence Listing

[0004] This application contains a sequence listing submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on December 8, 2020, is named 54462-712_601_SL.txt and is 4,087,518 bytes in size. Background Art

[0005] Cardiovascular and metabolic disorders are becoming increasingly numerous and can affect a wide variety of people. Improved therapies to treat these disorders are needed. Summary of the Invention

[0006] In some embodiments, disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 4 (ANGPTL4) and, when administered to a subject in an effective amount, reduce circulating triglycerides, reduce circulating glucose, increase circulating high-density lipoprotein (HDL), or increase insulin sensitivity, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13935 and having no more than 2 mismatches, and each strand having 12 to 30 nucleotides. In some embodiments, triglycerides, total cholesterol, or glucose are reduced by about 10% or more, or HDL or insulin sensitivity is increased by about 10% or more, as compared to before administration. In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13936 and has no more than 2 mismatches. In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to the antisense strand sequence of the siRNA in Table 4. In some embodiments, the antisense strand comprises a nucleoside sequence of the antisense strand sequence of the siRNA in Table 4, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence of the antisense strand sequence of the siRNA in Table 4. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to the sense strand sequence of the siRNA in Table 4. In some embodiments, the sense strand comprises a nucleoside sequence of the sense strand sequence of the siRNA in Table 4, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of the sense strand sequence of the siRNA in Table 4. In some embodiments, the antisense strand comprises a nucleoside sequence that is identical to SEQ ID NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987 , 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696 has at least 85% identical nucleotide sequence.In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 299 1, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186 ,2188,2338,2363,2373,2419,2424,2425,2474,2491,2494,2613,2688,2730,2855,2 987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696. In some embodiments, the sense strand comprises the nucleotide sequence of SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509 ,519,565,570,571,620,637,640,759,834,876,1001,1133,1134,1137,1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842 is at least 85% identical to a nucleotide sequence.In some embodiments, the sense strand comprises SEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154 , 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 5 09, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1 In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981. In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13970-13973. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage.In some embodiments, the modified internucleoside linkage comprises an alkylphosphonate, a thiophosphate, a methylphosphonate, a dithiophosphate, an alkylphosphonothioate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamidate or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises a thiophosphate linkage. In some embodiments, the sense strand comprises 2-6 modified internucleoside linkages. In some embodiments, the antisense strand comprises 2-6 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises modified nucleosides. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2',4' constrained ethyl, a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, a 2'-deoxy, a 2'O methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, a 2'ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'fluoro modified nucleoside. In some embodiments, the modified nucleoside comprises a 2'O methyl modified nucleoside. In some embodiments, the sense strand or the antisense strand comprises 15-21 modified nucleosides. In some embodiments, the sense strand or the antisense strand comprises a 3' overhang of at least 2 nucleosides. In some embodiments, the oligonucleotide comprises a GalNAc ligand attached to the 3' or 5' end of the sense strand. In some embodiments, the oligonucleotide comprises a GalNAc ligand attached to the 3' or 5' end of the antisense strand.In some embodiments, the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13954), modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 13955), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 13956), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3' (SEQ ID NO: 13957), modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnsnsnN-3' (SEQ ID NO: 13958). NO: 13958), modification pattern 6S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn 3' (SEQ ID NO: 13959); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside.In some embodiments, the antisense strand comprises modification pattern 1 AS: 5'nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 13960), modification pattern 2 AS: 5'nsNfsnnnNfNfnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13961), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13962), modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 13963), modification pattern 5 AS: 5'nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 13964). NO: 13964), modification pattern 6AS: 5'nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn 3' (SEQ ID NO: 13965), modification pattern 7AS: 5'nsNfsnNfnNfnNfnNfnnnnNfnnnsnsn 3' (SEQ ID NO: 13966), modification pattern 8AS: 5'nsNfsnnnnnnnnnnnNfnnnnnsnsn 3' (SEQ ID NO: 13967) or modification pattern 9AS: 5'nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn 3' (SEQ ID NO: 13968); wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution.

[0007] Disclosed herein are methods for treating a metabolic or cardiovascular disorder in a subject in need thereof, the methods comprising administering to the subject an effective amount of a composition comprising an oligonucleotide that targets ANGPTL4, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13936 and having no more than 2 mismatches, and each strand having 12 to 30 nucleotides. In some embodiments, the disorder comprises hyperlipidemia, hypertriglyceridemia, pancreatitis, familial chylomicronemia syndrome, diabetes, type 2 diabetes, heart disease, myocardial infarction, angina, or atherosclerosis. In some embodiments, the effective amount of the composition results in a decrease in a triglyceride measurement, a decrease in a cholesterol measurement, a decrease in a glucose measurement, an increase in a HDL measurement, or an increase in an insulin sensitivity measurement of the subject by about 10% or more relative to a baseline measurement. In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13935 and has no more than 2 mismatches. In some embodiments, the antisense strand comprises a siRNA that is complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13936 and has no more than 2 mismatches. NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987 , 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696 has at least 85% identical nucleotide sequence.In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 2994, 2995, 2996, 2997, 2998, 29 ... 91, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186 ,2188,2338,2363,2373,2419,2424,2425,2474,2491,2494,2613,2688,2730,2855,2 987, 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694, or 3696. In some embodiments, the sense strand comprises the nucleotide sequence of SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509 ,519,565,570,571,620,637,640,759,834,876,1001,1133,1134,1137,1149, 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842 is at least 85% identical to a nucleotide sequence.In some embodiments, the sense strand comprises SEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154 , 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 5 09, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1 In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981. In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13970-13973. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973.In some embodiments, the oligonucleotide comprises a modified internucleoside linkage comprising an alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises a modified nucleoside comprising a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2',4' constrained ethyl, a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, a 2'-deoxy, a 2'O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, a 2'ara-F, or a combination thereof. In some embodiments, the sense strand or antisense strand comprises a 3' overhang of at least two nucleosides. In some embodiments, the oligonucleotide comprises a GalNAc ligand attached to the 3' or 5' end of the sense strand. In some embodiments, the oligonucleotide comprises a GalNAc ligand attached to the 3' or 5' end of the antisense strand. In some embodiments, the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13954), modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 13955), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 13956), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3' (SEQ ID NO: 13957), modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnsnsnN-3' (SEQ ID NO: 13958). NO: 13958), modification pattern 6S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn 3' (SEQ ID NO: 13959); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside.In some embodiments, the antisense strand comprises modification pattern 1 AS: 5'nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 13960), modification pattern 2 AS: 5'nsNfsnnnNfNfnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13961), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13962), modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 13963), modification pattern 5 AS: 5'nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 13964). NO: 13964), modification pattern 6AS: 5'nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn 3' (SEQ ID NO: 13965), modification pattern 7AS: 5'nsNfsnNfnNfnNfnNfnnnnNfnnnsnsn 3' (SEQ ID NO: 13966), modification pattern 8AS: 5'nsNfsnnnnnnnnnnnNfnnnnnsnsn 3' (SEQ ID NO: 13967) or modification pattern 9AS: 5'nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn 3' (SEQ ID NO: 13968); wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

[0008] Disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 4 (ANGPTL4) and that, when administered to a subject in an effective amount, reduce circulating triglycerides. In some embodiments, triglycerides are reduced by about 10% or more, as compared to before administration. Also disclosed herein are compositions comprising oligonucleotides that target ANGPTL4 and that, when administered to a subject in an effective amount, reduce circulating total cholesterol. In some embodiments, total cholesterol is reduced by about 10% or more, as compared to before administration. Also disclosed herein are compositions comprising oligonucleotides that target ANGPTL4 and that, when administered to a subject in an effective amount, increase circulating high-density lipoprotein (HDL). In some embodiments, HDL is increased by about 10% or more, as compared to before administration. Also disclosed herein are compositions comprising oligonucleotides that target ANGPTL4 and that, when administered to a subject in an effective amount, reduce circulating glucose. In some embodiments, glucose is reduced by about 10% or more, as compared to before administration. Also disclosed herein are compositions comprising oligonucleotides that target ANGPTL4 and increase insulin sensitivity when administered to a subject in an effective amount. In some embodiments, insulin sensitivity is increased by about 10% or more compared to before administration. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 14-30 nucleosides in length. In some embodiments, the antisense strand is 14-30 nucleosides in length. Also disclosed herein are compositions comprising oligonucleotides that inhibit the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of SEQ ID NO: 13935. Also disclosed herein are compositions comprising oligonucleotides that inhibit the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of SEQ ID NO: 13936. In some embodiments, the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a sequence having 1 or 2 nucleoside substitutions,In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977. In some embodiments, the sense strand further comprises a 3' overhang comprising 1, 2 or more nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a nucleic acid sequence having 1 or 2 nucleosides substituted, added or deleted. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985. In some embodiments, the antisense strand further comprises a 3' overhang comprising 1, 2 or more nucleosides. In some embodiments, the siRNA binds to a 19-mer in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 17-mer in non-human primate ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 19-mer in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a human ANGPTL4 mRNA and fewer than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL4 mRNA target site that does not have a SNP (positions 2-18) with a minor allele frequency (MAF) greater than or equal to 1%. In some embodiments, the sense strand comprises SEQ ID NO: NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 12 9, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335,337、338、339、342、347、349、350、352、353、356、377、380、382、386、388、391、392、393、394、397、398、399、402、404、405、411、412、413、414、415、417、419、420、421、422、423、424、425、426、427、428、429、430、431、435、481、484、506、509、517、519、520、565、570、571、572、589、607、608、610、611、612、616、617、620、623、635、637、640、643、653、672、673、674、675、676、677、678、679、681、682、683、684、686、687、689、692、695、830、834、841、842、843、844、850、851、852、853、854、856、857、859、866、868、871、872、876、887、888、890、892、893、894、897、900、902、907、911、912、913、914、915、916、917、918、919、920、921、922、925、945、968、1001、1002、1005、1006、1009、1010、1011、1013、1028、1032、1037、1052、1053、1054、1055、1057、1058、1064、1112、1122、1124、1126、1127、1133、1134、1136、1137、1147、1148、1149、1151、1153、1154、1155、1157、1158、1161、1162、1163、1164、1165、1166、1171、1172、1175、1181、1182、1184、1248、1249、1252、1253、1259、1276、1285、1310、1315、1338、1343、1347、1348、1349、1350、1351、1352、1378、1405、1407、1413、1414、1415、1416、1417、1418、1429、1430、1448、1477、1487、1488、1489、1493、1494、1519、1523、1538、1556、1561、1563、1564、1565、1570、1571、1572、1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802 or 1803, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012 , 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107 107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2194 6. 2201, 2203, 2204, 2206, 2207, 2210, 2231, 2234, 2236, 2240, 2242, 2245, 2246, 2247, 2248, 2251, 2252, 2253, 2256, 2258, 2259, 2265, 2266, 2267, 2268, 2269, 2271, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281,2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911、2912、2918、2966、2976、2978、2980、2981、2987、2988、2990、2991、3001、3002、3003、3005、3007、3008、3009、3011、3012、3015、3016、3017、3018、3019、3020、3025、3026、3029、3035、3036、3038、3102、3103、3106、3107、3113、3130、3139、3164、3169、3192、3197、3201、3202、3203、3204、3205、3206、3232、3259、3261、3267、3268、3269、3270、3271、3272、3283、3284、3302、3331、3341、3342、3343、3347、3348、3373、3377、3392、3410、3415、3417、3418、3419、3424、3425、3426、3434、3435、3443、3451、3452、3455、3456、3457、3458、3459、3460、3464、3465、3467、3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises SEQ ID NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 116, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177, 196, 198, 199, 210, 211, 212、214、215、216、217、218、219、221、222、223、228、230、231、240、241、245、246、250、252、253、254、255、260、261、262、263、265、266、271、272、274、280、282、289、290、291、292、293、299、304、321、323、325、326、328、329、330、331、332、333 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853,854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1 055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310 , 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1590 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802, or 1803. In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983,2003、2004、2006、2007、2008、2011、2012、2013、2015、2018、2019、2020、2021、2022、2023、2026、2028、2029、2031、2050、2052、2053、2064、2065、2066、2068、2069、2070、2071、2072、2073、2075、2076、2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772, 2773, 2774, 2775, 2776, 2779, 2799, 2822, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2891, 2906, 2907, 2908, 2909, 2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 300 2. 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3207 32, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3460 458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NO:33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290, 291, 292, 293, 321, 32 3, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349 ,411,412,430,431,435,481,484,509,517,519,520,565,620,635,637 ,640,830,834,841,842,843,844,850,871,872,876,887,888,894,897,1784, or 1787, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand comprises SEQ ID NO: 1. NO:1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 219 2, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2688, 2695, 2696, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 30 20, 3025, 3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425, 3426, 3464, 3465, 3471, 3634, 3638 or 3641, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises SEQ ID NO: 32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129, 149, 150, 152, 153, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211,212、214、215、216、217、218、219、221、222、223、228、230、231、240、241、245、246、250、252、253、254、255、260、261、262、263、265、266、271、272、274、280、289、290、291、292、293、299、304、321、323、325、326、328、329、330、331、332、333、334、335、337、338、339、342、347、349、350、352、353、356、380、382、386、388、391、392、393、394、397、398、399、402、404、405、411、412、413、414、415、420、421、422、423、424、425、426、427、428、429、430、431、435、484、517、519、520、565、570、571、572、607、608、610、611、612、616、617、620、635、637、640、672、673、674、675、676、677、678、679、681、682、683、684、686、687、689、692、695、830、841、842、843、844、850、851、852、853、854、856、857、866、868、871、872、876、887、888、890、892、893、894、902、911、912、913、914、915、916、917、918、919、920、921、922、945、1001、1002、1005、1006、1009、1010、1011、1013、1028、1032、1052、1053、1054、1055、1057、1058、1112、1122、1124、1126、1127、1133、1134、1147、1148、1149、1151、1153、1154、1155、1157、1158、1161、1162、1164、1165、1166、1175、1182、1184、1252、1253、1259、1276、1285、1310、1315、1343、1347、1348、1349、1350、1351、1405、1407、1413、1414、1415、1416、1417、1418、1429、1430、1448、1519、1523、1556、1784, 1788, 1798, 1799, 1801, 1802 or 1803, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1966, 1970, 1971, 1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2011, 2012, 2013, 2015, 2018, 2019, 19, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117 7, 2119, 2120, 2125, 2126, 2128, 2134, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2234 、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2338、2371、2373、2374、2419、2424, 2425, 2426, 2461, 2462, 2464, 2465, 2466, 2470, 2471, 2474, 2489, 2491, 2494, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2535, 2536, 2537, 2538, 2540, 2541, 2543, 2546, 2549, 2684, 2695, 2696, 2697, 2698, 2704, 2705, 2706, 2707, 2708, 2710, 2711, 2720, 2722, 2725, 27 26, 2730, 2741, 2742, 2744, 2746, 2747, 2748, 2756, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2799, 2855, 2856, 2859, 2860, 2863, 2864, 2865, 2867, 2882, 2886, 2906, 2907, 2908, 2909, 2911, 2912, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 3001, 3002 , 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3029, 3036, 3038, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3197, 3201, 3202, 3203, 3204, 3205, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3373, 3377, 3410, 3415, 3417, 3418, 3419, 3634, 3638, 3642, 3652, 3653, 3655, 3656, or 3657, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises SEQ ID NO: 33, 34, 35, 36, 56, 272, 280, 289, 290, 291, 292, 293, 321,323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435, 484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842, 843, 844, 850, 871, 872, 876, 887, 888, 894, 902, 945 , 1001, 1002, 1005, 1133, 1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780, or 1784, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises SEQ ID NO: NO:1887, 1888, 1889, 1890, 1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 21 89, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2695, 269 6, 2697, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2756, 2799, 2855, 2856, 2859, 2987, 2988, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a seed region that is different from the seed region of the human miRNA. In some embodiments, the sense strand comprises SEQ ID NO: 32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217,218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291, 292, 293, 304, 321, 323, 325, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 352, 353, 356, 380, 382, ​​386, 388, 391, 392, 394, 399, 4 13, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679, 681, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892, 893, 902, 911, 912 、913、914、916、919、945、1001、1002、1006、1010、1028、1052、1053、1054、1055、1057、1112、1124、1127、1147、1149、1151、1153、1155、1157、1164、1175、1182、1184、1259、1276、1285、1315、1343、1349、1350、1351、1 405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722, 1740, 1745, 1751, 1755, 1801, 1802 or 1803 or 3638, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO:1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971, 1973, 1979, 1980 , 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020, 2021, 2022, 2023, 2028, 2 050, 2065, 2066, 2071, 2072, 2073, 2084, 2085, 2099, 2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146, 2147, 2158, 2175, 2177, 2179, 2180, 2182,2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2206, 2207, 2210, 2234, 2236, 2240, 2242, 2245, 2246, 2248, 2253, 2267, 2268, 2269, 2276, 2277, 2278, 2279, 2280, 2289, 2371, 2373, 2374, 2419, 2420 425, 2461, 2462, 2466, 2471, 2474, 2489, 2494, 2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546, 2696, 2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765, 2766, 2767, 2768, 27 70, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906, 2907, 2908, 2909, 2911, 2966, 2978, 2981, 3001, 3003, 3005, 3007, 3009, 3011, 3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204, 3205, 325 9, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599, 3605, 3609, 3655, 3656 or 3657, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises the nucleotide sequence of any one of SEQ ID 36, 56, 272, 280, 289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843, 850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164, 1315, 1343, or 1571, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand comprises SEQ ID: 1890, 1910, 2126, 2134, 2143, 2145, 2146, 2147,3009, 3011, 3018, 3169, 3197, or 3425, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a seed region that is different from the seed region of a human miRNA. In some embodiments, the sense strand comprises SEQ ID NO: 32, 36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158, 159, 161, 166, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260, 261, 271, 272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349, 353, 356, 386, 388, 391, 392, 394, 414, 415, 422, 423, 424, 426, 435, 520, 571, 608, 612, 6 17, 653, 672, 678, 679, 681, 683, 692, 842, 843, 851, 854, 859, 876, 892, 900, 913, 914, 919, 968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157, 1164, 1182, 1184, 1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581, 1602, 1614, 1693, 1701, 1722, 1740, 1751, 1755 or 1787, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO: 1886, 1890, 1910, 1912, 1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013, 2015, 2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099, 2107, 2114, 2115, 2125, 2126, 2134, 2143, 2147,2158, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242, 2245, 2246, 2248, 2268, 2269, 2276, 2277, 2278, 2280, 2289, 2374, 2425, 2462, 2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697, 2705, 2708, 2713, 27 30, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856, 2908, 2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197, 3205, 3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594, 3605, 3609 or 3641, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NO: 36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697, 2730, 2855, 2856, 3011, 3018, or 3197, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand and / or antisense strand further comprises a nucleotide sequence comprising 1,2 or more 3' overhangs of nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises an alkylphosphonate, a thiophosphate, a methylphosphonate, a dithiophosphate, an alkylthiophosphonate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamidate or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more thiophosphate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro or a 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleosides include 2',4' constrained ethyl nucleic acids. In some embodiments, the modified nucleosides include 2'-O-methyl nucleosides, 2'-deoxyfluoro nucleosides, 2'-ON-methylacetamido (2'-O-NMA) nucleosides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleosides,2'-O-aminopropyl (2'-O-AP) nucleosides or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleosides include one or more 2' fluorine-modified nucleosides. In some embodiments, the modified nucleosides include 2'O-alkyl-modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenyl, docosahexaenoyl, myristyl, palmitylstearyl or α-tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides,or 21 or more modified nucleosides. In some embodiments, the sense strand comprises modification pattern 1S. In some embodiments, the sense strand comprises modification pattern 2S. In some embodiments, the sense strand comprises modification pattern 3S. In some embodiments, the sense strand comprises modification pattern 4S. In some embodiments, the sense strand comprises modification pattern 5S. In some embodiments, the sense strand comprises modification pattern 6S. In some embodiments, any of modification patterns 1S-6S may comprise a GalNAc ligand at the 5' or 3' end. In some embodiments, the antisense strand comprises modification pattern 1AS. In some embodiments, the antisense strand comprises modification pattern 2AS. In some embodiments, the antisense strand comprises modification pattern 3AS. In some embodiments, the antisense strand comprises modification pattern 4AS. In some embodiments, the antisense strand comprises modification pattern 5AS. In some embodiments, the antisense strand comprises modification pattern 6AS. In some embodiments, the antisense strand comprises modification pattern 7AS. In some embodiments, the antisense strand comprises modification pattern 8AS. In some embodiments, the antisense strand comprises modification pattern 9AS. Any of the modification patterns 1AS-9AS may include a GalNAc ligand at the 5' or 3' end. In some embodiments, the sense strand comprises modification pattern 1S, and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 2S, and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 3S, and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 4S, and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises the modification pattern 5S and the antisense strand comprises the modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a sequence having 1 or 2 nucleoside substitutions,In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; and modification pattern 1S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions therefrom; and modification pattern 2S. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions therefrom; and modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a sequence having 1 or 2 nucleoside substitutions,In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 and a modification pattern 3AS. In some embodiments, the oligonucleotide comprises an ASO. In some embodiments, the ASO is 12-30 nucleosides in length. Also disclosed herein are compositions comprising oligonucleotides that inhibit the expression of ANGPTL4, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO) having a length of about 12-30 nucleosides and comprising a nucleoside sequence complementary to about 12-30 consecutive nucleosides of SEQ ID NO: 13935; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. Also disclosed herein are compositions comprising oligonucleotides that inhibit the expression of ANGPTL4, wherein the oligonucleotide comprises an ASO having a length of about 12-30 nucleosides and comprising a nucleoside sequence complementary to about 12-30 consecutive nucleosides of SEQ ID NO: 13936; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934; or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934. In some embodiments, the ASO comprises the modification pattern: 5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3', wherein "dN" is any deoxynucleotide, "n" is a 2'O-methyl or 2'O-methoxyethyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the ASO comprises one or more of a locked nucleic acid (LNA) or a 2',4' constrained ethyl nucleic acid. In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NOs: 3709-13934; or a sequence having 1 or 2 nucleoside substitutions,In some embodiments, the ASO comprises a nucleotide sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 3709-13934; and a modification pattern ASO1. In some embodiments, the ASO comprises a nucleotide sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 3709-13934. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. Some embodiments comprise a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution.

[0009] DETAILED DESCRIPTION

[0010] Large-scale human genetics data can improve the success rate of drug discovery and development. Genome-wide association studies (GWAS) can detect the association between genetic variants and traits in population samples. GWAS can enable a better understanding of the biology of the disease and provide applicable treatment methods. GWAS can utilize genotyping and / or sequencing data and generally involves the evaluation of millions of genetic variants that are relatively evenly distributed on the genome. The most common GWAS design is a case-control study, which involves comparing the frequency of variants in cases relative to controls. If a variant has a significantly different frequency in cases relative to controls, the variant is said to be associated with the disease. The association statistics that can be used in GWAS are p-values ​​as a measure of statistical significance; odds ratios (ORs) as a measure of effect size; or beta coefficients (βs) as a measure of effect size. Researchers usually assume an additive genetic model and calculate the allelic odds ratio, which is the increased (or decreased) disease risk conferred by each additional allele copy (compared to not carrying the allele copy). Another concept in GWAS design and interpretation is linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium may obfuscate which variant is "causal."

[0011] Functional annotation of variants and / or wet laboratory experiments can identify the causal genetic variants identified via GWAS, and in many cases may lead to the identification of disease-causing genes. In particular, understanding the functional effects of causal genetic variants (e.g., loss of protein function, gain of protein function, increase in gene expression, or reduction in gene expression) can allow the variant to be used as a representative for therapeutic regulation of the target gene, or to gain a deeper understanding of the potential therapeutic efficacy and safety of the therapeutic agent that regulates the target.

[0012] The identification of such gene-disease associations has provided insights into disease biology and can be used to identify novel therapeutic targets for the pharmaceutical industry. In order to transform therapeutic insights derived from human genetics, the disease biology in patients can be exogenously "programmed" to replicate observations from human genetics. There are several potential treatment options that can be utilized in converting therapeutic targets identified via human genetics into novel drugs. These can include well-established treatment modalities, such as small molecules and monoclonal antibodies; mature approaches, such as oligonucleotides; and emerging approaches, such as gene therapy and gene editing. The choice of treatment modality can depend on several factors, including the location of the target (e.g., intracellular, extracellular, or secreted), relevant tissues (e.g., liver), and relevant indications.

[0013] Cardiovascular and metabolic diseases are the leading causes of death, accounting for approximately one-third of all deaths worldwide. Angiopoietin-like proteins (ANGPTLs) are regulators of lipoprotein metabolism and serve as therapeutic targets for modulating lipid levels and cardiometabolic disease risk. ANGPTLs are a family of eight proteins that share some functional similarities with angiopoietin. They generally share a characteristic structure that includes an N-terminal coiled-coil domain that mediates homo-oligomerization and a C-terminal fibrinogen domain involved in signaling.

[0014] Angiopoietin-like 4 (ANGPTL4; UniProt ID Q9BY76) is an endogenous inhibitor of lipoprotein lipase (LPL), an enzyme that hydrolyzes triglycerides contained in triglyceride-rich lipoproteins (TRLs), such as chylomicrons and very-low-density lipoproteins. ANGPTL4 is a secreted protein that, in humans, is typically most highly expressed in the liver and adipose tissue. Following cellular secretion, ANGPTL4 is typically cleaved into a 37 kD C-terminal fragment and a 15 kD N-terminal fragment, and these oligomerized N-terminal fragments inhibit LPL. In some embodiments, ANGPTL4 is glycosylated. In some embodiments, ANGPTL4 has a coiled-coil N-terminal domain. In some embodiments, ANGPTL4 has a fibrinogen-like C-terminal domain.

[0015] Circulating triglycerides are strong, independent, and positive predictors of cardiovascular disease risk and all-cause mortality, and are also positively correlated with plasma glucose levels, diabetes risk, metabolic syndrome, and pancreatitis. Furthermore, mutations in TRL genes may cause inherited disorders, including familial chylomicronemia syndrome and familial hypertriglyceridemia. Here, genetic variants that inactivate ANGPTL4 in humans have been shown to be associated with decreased triglycerides, increased HDL, and a reduced risk of diabetes and cardiovascular disease. Therefore, inhibition of ANGPTL4 may serve as a therapeutic strategy for treating a range of cardiometabolic diseases.

[0016] Disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 4 (ANGPTL4). The oligonucleotides may include small interfering RNA (siRNA) or antisense oligonucleotides (ASOs). Also provided herein are methods for treating metabolic or cardiovascular disorders by providing an oligonucleotide targeting ANGPTL4 to a subject in need thereof.

[0017] I. Composition

[0018] In some embodiments, disclosed herein are compositions comprising oligonucleotides. In some embodiments, the compositions comprise oligonucleotides that target angiopoietin-like 4 (ANGPTL4). In some embodiments, the compositions consist of oligonucleotides that target ANGPTL4. In some embodiments, the compositions described herein are used in a method of treating a condition in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in a method of treating a condition as described herein. Some embodiments relate to the use of a composition comprising an oligonucleotide in a method of treating a condition as described herein.

[0019] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces ANGPTL4 mRNA levels in a cell or tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the tissue is liver or adipose tissue. In some embodiments, ANGPTL4 mRNA levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by about 10% or more, as compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by no more than about 10% compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90% compared to before administration. In some embodiments, ANGPTL4 mRNA levels are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces circulating ANGPTL4 protein levels in a cell or tissue. In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces ANGPTL4 protein levels in a fluid (such as blood, serum, or plasma). In some embodiments, ANGPTL4 protein levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by about 10% or more, as compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by no more than about 10% compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90% compared to before administration. In some embodiments, ANGPTL4 protein levels are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces circulating triglycerides. In some embodiments, triglycerides are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, triglycerides are reduced by about 10% or more, as compared to before administration. In some embodiments, triglycerides are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, triglycerides are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to before administration. In some embodiments, triglycerides are reduced by no more than about 10%, as compared to before administration. In some embodiments, triglycerides are reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90% compared to before administration. In some embodiments, triglycerides are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any two of the foregoing percentages.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces circulating cholesterol. In some embodiments, circulating cholesterol includes circulating total cholesterol. In some embodiments, circulating cholesterol is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, circulating cholesterol is reduced by about 10% or more, as compared to before administration. In some embodiments, circulating cholesterol is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, cholesterol is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to before administration. In some embodiments, cholesterol is reduced by no more than about 10%, as compared to before administration. In some embodiments, cholesterol is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to before administration. In some embodiments, circulating cholesterol is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any two of the foregoing percentages.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, increases circulating high-density lipoprotein (HDL). In some embodiments, circulating HDL increases by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, circulating HDL increases by about 10% or more, as compared to before administration. In some embodiments, circulating HDL increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to before administration. In some embodiments, circulating HDL increases by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to before administration. In some embodiments, HDL is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, HDL is reduced by no more than about 10% compared to before administration. In some embodiments, HDL is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before administration. In some embodiments, HDL is reduced by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% compared to before administration. In some embodiments, circulating HDL is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by any two of the foregoing percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces circulating glucose. In some embodiments, circulating glucose is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, circulating glucose is reduced by about 10% or more, as compared to before administration. In some embodiments, circulating glucose is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, glucose is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to before administration. In some embodiments, glucose is reduced by no more than about 10%, as compared to before administration. In some embodiments, glucose is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90% as compared to before administration. In some embodiments, circulating glucose is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any two of the foregoing percentages.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and increases insulin sensitivity when administered to a subject in an effective amount. In some embodiments, insulin sensitivity is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, insulin sensitivity is increased by about 10% or more, as compared to before administration. In some embodiments, insulin sensitivity is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to before administration. In some embodiments, insulin sensitivity is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to before administration. In some embodiments, insulin sensitivity is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5% as compared to before administration. In some embodiments, insulin sensitivity is increased by no more than about 10% as compared to before administration. In some embodiments, insulin sensitivity is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% as compared to before administration. In some embodiments, insulin sensitivity is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% as compared to before administration. In some embodiments, insulin sensitivity is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by any two of the foregoing percentages.

[0026] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and, when administered to a subject in an effective amount, reduces circulating insulin. In some embodiments, circulating insulin is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to before administration. In some embodiments, circulating insulin is reduced by about 10% or more, as compared to before administration. In some embodiments, circulating insulin is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% as compared to before administration. In some embodiments, insulin is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to before administration. In some embodiments, insulin is reduced by no more than about 10%, as compared to before administration. In some embodiments, insulin is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90% as compared to before administration. In some embodiments, circulating insulin is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any two of the foregoing percentages.

[0027] A.siRNA

[0028] In some embodiments, the composition comprises an oligonucleotide targeting angiopoietin-like 4 (ANGPTL4), wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting angiopoietin-like 4 (ANGPTL4), wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand comprises RNA. In some embodiments, the antisense strand comprises RNA.

[0029] In some embodiments, the siRNA comprises a sense strand and an antisense strand, the antisense strand is complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 13936 and has no more than 2 mismatches, and each strand has 12 to 30 nucleotides. In some embodiments, the siRNA comprises a sense strand and an antisense strand, the antisense strand is complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 13935 and has no more than 2 mismatches, and each strand has 12 to 30 nucleotides.

[0030] In some embodiments, the siRNA comprises a sense strand and an antisense strand, the antisense strand is 100% complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13936, and each strand has 12 to 30 nucleotides. In some embodiments, the siRNA comprises a sense strand and an antisense strand, the antisense strand is 100% complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 13935, and each strand has 12 to 30 nucleotides.

[0031] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 14-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers. In some embodiments, the composition comprises an antisense strand that is 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of a full-length human ANGPTL4 mRNA sequence, such as SEQ ID NO: 13935. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 13935.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of the full-length human ANGPTL4 pre-mRNA sequence of SEQ ID NO: 13936. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 13936.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleosides added to the 3' end. The sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 may include the sequence of any one of SEQ ID NOs: 1-1854. The sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 may include the sequence of any one of SEQ ID NOs: 13970-13977.

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of: a sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises a nucleotide sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, or a nucleic acid sequence having 1 or 2 nucleosides added to the 3' end. The sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 may include the sequence of any one of SEQ ID NOs: 1855-3708. The sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 may include the sequence of any one of SEQ ID NOs: 13978-13985.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer of human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer of human ANGPTL4 mRNA.

[0040] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 17-mer of non-human primate ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer of non-human primate ANGPTL4 mRNA.

[0041] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer or a combination thereof in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in human ANGPTL4 mRNA.

[0042] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 20 human off-targets, wherein the antisense strand has no more than 2 mismatches. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 10 human off-targets, and has no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 30 human off-targets, and has no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 40 human off-targets, and has no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 50 human off-targets, and has no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0043] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a human ANGPTL4 mRNA target site that does not have a SNP (positions 2-18) with a minor allele frequency (MAF) greater than or equal to 1%. In some embodiments, the MAF is greater than or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0044] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:32,33,34,35,36,56,57,58,59,61,62,63,64,79,80,84,111,112,116,117,118,119,120,121,125,126,127,128,129,149,150,152,1 53, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175 ,177,196,198,199,210,211,212,214,215,216,217,218,219,221,2 22, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 387 8, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673 , 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945,968, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158 , 1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417 7, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1 617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802 or 1803, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions; and / or the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 19 18, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 198 0, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064,2065、2066、2068、2069、2070、2071、2072、2073、2075、2076、2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911, 2912, 2918, 2966, 2976, 2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3037 038, 3102, 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 33 42, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 355 3, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656 or 3657, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof.

[0045] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:32,33,34,35,36,56,57,58,59,61,62,63,64,79,80,84,111,112,116,117,118,119,120,121,125,126,127,128,129,149,150,152,1 53, 154, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175 ,177,196,198,199,210,211,212,214,215,216,217,218,219,221,2 22, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 387 8, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673 , 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945,968, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1156 7, 1158, 1161, 1162, 1163, 1164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1 415, 1416, 1417, 1418, 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 161 0, 1611, 1613, 1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802 or 1803; and / or the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 19 33, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 198 2. 1983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069,2070、2071、2072、2073、2075、2076、2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911、2912、2918、2966、2976、2978、2980、2981、2987、2988、2990、2991、3001、3002、3003、3005、3007、3008、3009、3011、3012、3015、3016、3017、3018、3019、3020、3025、3026、3029、3035、3036、3038、3102、 3103, 3106, 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342、3343、3347、3348、3373、3377、3392、3410、3415、3417、3418、3419、3424、3425、3426、3434、3435、3443、3451、3452、3455、3456、3457、3458、3459、3460、3464、3465、3467、3468、 The nucleotide sequence of any one of 3471, 3547, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656 or 3657.

[0046] In some embodiments, the sense strand comprises SEQ ID NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 11 6, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 154 ,157,158,159,161,164,165,166,167,168,169,172,174,175,177,196, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 23 0, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 388, 391, 392, 393, 394, 397, 398 、399、402、404、405、411、412、413、414、415、417、419、420、421、422、423、424、425、426、427、428、429、430、431、435、481、484、506、509、517、519、5 20, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894 4, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028,1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164, 1165, 1166, 117 1, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1 448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613, 1614, 1617 , 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802, or 1803, or a nucleic acid sequence having 1 or 2 nucleosides added to the 3' end thereof. In some embodiments, the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934 ,1938,1965,1966,1970,1971,1972,1973,1974,1975,1979,1980,1981,1982,1983,2003,2 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075,2076、2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911、2912、2918、2966、2976、2978、2980、2981、2987、2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3130 , 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348, 337 3, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555, 3561 56, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657, or a nucleic acid sequence having 1 or 2 nucleoside additions at the 3' end. For example, the nucleic acid sequence may have 2 uridine additions at the 3' end. The nucleic acid sequence may have 1 uridine addition at the 3' end. The nucleic acid sequence may have more than 2 nucleoside additions at the 3' end.

[0047] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342 ,347,349,411,412,430,431,435,481,484,509,517,519,520,565,620,635,637,640,830,834,841,842,843,844,850,871,872,876,8 the nucleotide sequence of any one of 87, 888, 894, 897, 902, 945, 1001, 1002, 1005, 1037, 1133, 1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338, 1343, 1347, 1348, 1429, 1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780, 1784, or 1787;and / or the antisense strand comprises SEQ ID NO: 1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 21 91, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2688, 2695, 2696, 2697 7, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015 , 3016, 3018, 3019, 3020, 3025, 3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425, 3426, 3464, 3465, 3471, 3634, 3638, or 3641. ;

[0048] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:32,33,34,35,36,56,57,58,59,61,62,63,64,79,80,112,116,117,118,119,120,125,126,127,128,129,149,150,152,153,157,158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211, 21 2. 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 380, 382, ​​386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 403 04, 405, 411, 412, 413, 414, 415, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 484, 517, 519, 520, 565, 570, 571, 572, 607, 608, 610, 611, 612, 616, 617, 620, 635, 637, 640, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 841, 84 2, 843, 844, 850, 851, 852, 853, 854, 856, 857, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 902, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055, 1057, 1058, 1112, 1122, 1124,1126、1127、1133、1134、1147、1148、1149、1151、1153、1154、1155、1157、1158、1161、1162、1164、1165、1166、1175、1182、1184、1252、1253、1259、1276、1285、1310、1315、1343、1347、1348、1349、1350、1351、1405、1407、1413、1414、1415、1416、1417、1418、1429、1430、1448、1519、1523、1556 1561, 1563, 1564, 1565, 1571, 1572, 1580, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802, or 1803; and / or the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1 918, 1933, 1934, 1966, 1970, 1971, 1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2003, 2004, 2006, 2007, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071 1, 2072, 2073, 2075, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2 128, 2134, 2143, 2144, 2145, 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201,2203、2204、2206、2207、2210、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2338、2371、2373、2374、2419、2424、2425、2426、2461、2462、2464、2465、2466、2470、2471、2474、2489、2491、2494、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2756、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2799、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2906、2907、2908、2909、2911、2912、2966、2976、2978、2980、2981、2987、2988、3001、3002、3003、3005、3007、3008、3009、3011、3012、3015、3016、3018、3019、3020、3029、3036、3038、3106、3107、3113、3130、3139、3164、3169、3197、3201、3202、3203、3204、3205、3259、3261、3267、3268、3269、3270、3271、3272、3283、3284、3302、3373、3377、3410、3415、3417、3418、3419、3425、3426、3434、3435、3443、3451、3455、3456、3457、3458、3459、3460、3465、3467、3468、3547、3553、3555、3556、The nucleotide sequence of any one of 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3642, 3652, 3653, 3655, 3656 or 3657.

[0049] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO: 33, 34, 35, 36, 56, 272, 280, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435, 484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842, 843, 844, 850 , 871, 872, 876, 887, 888, 894, 902, 945, 1001, 1002, 1005, 1133, 1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780, or 1784; and / or the antisense strand comprises the nucleotide sequence of any one of SEQ ID NO:1887, 1888, 1889, 1890, 1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2 188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

[0050] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO: 32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217, 218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291, 292, 293, 304, 321, 323, 325, 326 6, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 352, 353, 356, 380, 382, ​​386, 388, 391, 392, 394, 399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679, 68 1, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892, 893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006, 1010, 1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149, 1151, 1153, 1155, 1157, 1164, 1175, 1182, the nucleotide sequence of any one of 1184, 1259, 1276, 1285, 1315, 1343, 1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722, 1740, 1745, 1751, 1755, 1801, 1802, or 1803, or 3638;and / or the antisense strand comprises SEQ ID NO: 1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971, 1973, 1979, 1980, 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020, 2021, 2022, 2023, 2028, 2050, 2065, 2066, 2071, 2072, 2073, 2084, 2085, 2099, 2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146 、2147、2158、2175、2177、2179、2180、2182、2184、2185、2186、2187、2188、2191、2192、2196、2201、2203、2206、2207、2210、2234、2236、2240、2242、2245、2246、2248、2253、2267、2268、2269、2276、2277、2278、2279、2280、2289、2371、2373、2374、2419、2425、2461、2462、2466、2471、2 474, 2489, 2494, 2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546, 2696, 2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765, 2766, 2767, 2768, 2770, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906, 2907, 2908, 2909, 2911, 2966, 2978, 2981, 3001, 300 3. the nucleotide sequence of any one of 3005, 3007, 3009, 3011, 3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204, 3205, 3259, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599, 3605, 3609, 3655, 3656, or 3657.

[0051] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the sense strand comprising SEQ ID NO: 36, 56, 272, 280, 289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843, 850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164, 1315, 1343, or 1571; and / or the antisense strand comprises SEQ ID 1890, 1910, 2126, 2134, 2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371, 2373, 2374, 2419, 2474, 2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799, 2855, 2856, 3003, 3005, 3007, 3009, 3011, 3018, 3169, 3197, or 3425.

[0052] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:32, 36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158, 159, 161, 1 66, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260, 261, 27 1. 272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349 ,353,356,386,388,391,392,394,414,415,422,423,424,426,435,520,5 the nucleotide sequence of any one of 71, 608, 612, 617, 653, 672, 678, 679, 681, 683, 692, 842, 843, 851, 854, 859, 876, 892, 900, 913, 914, 919, 968, 1001, 1002, 1054, 1057, 1064, 1112, 1124, 1157, 1164, 1182, 1184, 1248, 1259, 1343, 1351, 1352, 1415, 1418, 1564, 1581, 1602, 1614, 1693, 1701, 1722, 1740, 1751, 1755, or 1787;and / or the antisense strand comprises SEQ ID NO: 1886, 1890, 1910, 1912, 1915, 1916, 1934, 1971, 1973, 1980, 2006, 2008, 2011, 2012, 2013, 2015, 2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099, 21 07, 2114, 2115, 2125, 2126, 2134, 2143, 2147, 2158, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2207, 2210, 2240, 2242, 2245, 2246, 2248, 2268, 2269, 2276, 227 7, 2278, 2280, 2289, 2374, 2425, 2462, 2466, 2471, 2507, 2526, 2532, 2533, 2535, 2537, 2546, 2696, 2697, 2705, 2708, 2713, 2730, 2746, 2754, 2767, 2768, 2773, 2822, 2855, 2856 , 2908, 2911, 2918, 2966, 2978, 3011, 3018, 3036, 3038, 3102, 3113, 3197, 3205, 3206, 3269, 3272, 3418, 3435, 3456, 3468, 3547, 3555, 3576, 3594, 3605, 3609, or 3641. ;

[0053] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NO: 36, 56, 272, 280, 289, 293, 328, 330, 331, 332, 333, 334, 337, 342, 347, 349, 435, 520, 842, 843, 876, 1001, 1002, 1157, 1164, or 1343; and / or the antisense strand comprises a siRNA comprising a sense strand and an antisense strand. The nucleotide sequence of any one of NO: 1890, 1910, 2126, 2134, 2143, 2147, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2196, 2201, 2203, 2289, 2374, 2696, 2697, 2730, 2855, 2856, 3011, 3018 or 3197.

[0054] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset A. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0055] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 4. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0056] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset B. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0057] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset C. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0058] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset D. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0059] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset E. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0060] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset F, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNAs of subset F. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0061] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA of subset G. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0062] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 5, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 5, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of the siRNA in Table 5. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 5. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 5. In some embodiments, the siRNA is unmodified. In some embodiments, the sense strand sequence of the siRNA in Table 5 comprises a modification pattern of 1S. In some embodiments, the sense strand sequence of the siRNA in Table 5 comprises a modification pattern of 3S or 6S. In some embodiments, the sense strand sequence of the siRNA in Table 5 comprises a modification pattern of 1AS. In some embodiments, the sense strand sequence of the siRNA in Table 5 comprises the modification pattern 4AS, 5AS, 7AS, or 8AS.

[0063] In some embodiments, the siRNA reduces ANGPTL mRNA measurements by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more relative to a control. In some embodiments, the siRNA reduces ANGPTL mRNA measurements by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, or 90% or less relative to a control. In some embodiments, the reduction is in a cell line such as U-138MG cells. In some embodiments, the reduction is in response to 1 nM of the siRNA. In some embodiments, the reduction is in response to 10 nM of the siRNA.

[0064] Some of the siRNAs in Table 5 reduced ANGPTL mRNA measurements by 10% or more relative to the control. In some embodiments, the siRNAs include ETD00646, ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD00692, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692, ETD00699, ETD00691 ...9, ETD00691, ETD00692, ETD00699, ETD00691, ETD0069 743, or a sense and / or antisense strand sequence of ETD00744, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA includes ETD00646, ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD00692, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692, ETD00699, ETD00691, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692, ETD00699, ETD00699, ETD00691, ETD00693, ETD00699, ETD00691, ETD00692, ETD00699, ETD00699, ETD00691, ETD00692, ETD00699, ETD00699, ETD00699, ETD00691, ETD00692, ETD0069 743, or a sense and / or antisense strand sequence of ETD00744, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.In some embodiments, the siRNA includes ETD00646, ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD00692, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00699, ETD00691, ETD00691, ETD00692, ETD00697, ETD00698, ETD00699, ETD00691, ETD00699, ETD00691, ETD00692, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00699 or ETD00743. In some embodiments, the siRNA comprises ETD00646, ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD0069 2. one or more of the internucleoside linkages and / or nucleoside modifications of ETD00694, ETD00702, ETD00709, ETD00713, ETD00714, ETD00715, ETD00716, ETD00717, ETD00719, ETD00721, ETD00726, ETD00727, ETD00728, ETD00729, ETD00730, ETD00731, ETD00733, ETD00736, ETD00738, or ETD00743.In some embodiments, the siRNA comprises ETD00646, ETD00648, ETD00649, ETD00651, ETD00653, ETD00654, ETD00655, ETD00656, ETD00658, ETD00660, ETD00661, ETD00662, ETD00667, ETD00669, ETD00683, ETD00684, ETD00686, ETD00688, ETD00689, ETD00691, ETD In some embodiments, the siRNA is unmodified.

[0065] The siRNA may comprise an unmodified form of the sense strand sequence of the siRNA listed in Table 5. In some embodiments, the siRNA listed in Table 5 comprises any sense strand sequence of the subset A siRNA that cross-reacts with NHP ANGPTL4 mRNA. The siRNA may comprise an unmodified form of the antisense strand sequence of the siRNA listed in Table 5. In some embodiments, the siRNA listed in Table 5 comprises any antisense strand sequence of the subset A siRNA that cross-reacts with NHP ANGPTL4 mRNA.

[0066] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 6, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 6, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 6. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 6. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 6. In some embodiments, the siRNA is unmodified.

[0067] The siRNA may comprise an unmodified form of the antisense strand sequence of the siRNA listed in Table 6. In some embodiments, the siRNA comprises the sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840 or 1842, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840 or 1842, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840 or 1842. The siRNA may comprise a sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840, or 1842, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840, or 1842, and a modification pattern described herein. For example, any of the sense strands comprising the sequence of SEQ ID NO: 32, 570, 571, 572, 589, 607, 759, 801, 1276, 1285, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1702, 1840, or 1842 can, in some cases, comprise modification patterns 1S, 2S, 3S, or 6S.

[0068] The siRNA may comprise an unmodified form of the antisense strand sequence of the siRNA listed in Table 6. In some embodiments, the siRNA comprises the antisense strand sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694 or 3696, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the antisense strand sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694 or 3696, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the antisense strand sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694, or 3696. The siRNA may comprise the antisense strand sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694, or 3696, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA can comprise the antisense sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694 or 3696, and a modification pattern described herein. For example, any of the antisense strands comprising the sequence of SEQ ID NO: 1886, 2424, 2425, 2426, 2443, 2461, 2613, 2655, 3130, 3139, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3556, 3694 or 3696 can comprise modification pattern 1AS, 3AS, 4AS, 5AS, 7AS or 8AS.

[0069] Some of the siRNAs in Table 6 reduced ANGPTL mRNA measurements by 10% or more relative to the control. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of ETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of ETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of ETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of ETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of ETD00915, ETD00916, ETD00917, ETD00921, ETD00924, ETD00925, ETD00926, ETD00927, ETD00928, ETD00929, ETD00930, ETD00931, ETD00932, ETD00933, or ETD00934. In some embodiments, the siRNA is unmodified.

[0070] The siRNA can comprise a sense strand sequence of an siRNA that reduces ANGPTL mRNA measurements by 10% or more relative to a control in Table 5 or Table 6. In some embodiments, the siRNA comprises SEQ ID NO: 14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083, 14085, 14086 7, 14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132, or 14133, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises SEQ ID NO: NO:14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083, 14085, 1408 7, 14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132 or 14133, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the siRNA comprises SEQ ID NO: 14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083 3. the sense strand sequence of any one of 14085, 14087, 14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132, or 14133. In some embodiments, the siRNA comprises 14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083 3, 14085, 14087, 14092, 14093, 14094, 14095, 14096, 14097, 14099, 14102, 14104, 14109, 14114, 14115, 14116, 14120, 14123, 14124, 14125, 14126, 14127, 14128, 14129, 14130, 14131, 14132, or 14133 of the sense strand.In some embodiments, the siRNA comprises 14012, 14014, 14015, 14017, 14019, 14020, 14021, 14022, 14024, 14026, 14027, 14028, 14033, 14035, 14049, 14050, 14052, 14054, 14055, 14057, 14058, 14060, 14068, 14075, 14079, 14080, 14081, 14082, 14083, 14084, 14085, 14086, 14087, 14088, 14090, 14091, 14092, 14093, 14094, 14095, 14096, 14097, 14098, 14099, 14091, 14092, 14093, 14094, 14095, 14097, 14098 14129, 14130, 14131, 14132, or 14133. In some embodiments, the siRNA is unmodified.

[0071] The siRNA can comprise an antisense strand sequence of an siRNA that reduces ANGPTL mRNA measurements by 10% or more relative to a control in Table 5 or Table 6. In some embodiments, the siRNA comprises SEQ ID NO: 14167, 14169, 14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236, 14237, 14238, 14240, 14241 2, 14247, 14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287 or 14288, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises SEQ ID NO: NO:14167, 14169, 14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236, 14237, 14238, 14240, 1424 2, 14247, 14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287 or 14288, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the siRNA comprises SEQ ID NO: 14167, 14169, 14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236, 14237, 14238 8, the antisense sequence of any one of 14240, 14242, 14247, 14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287 or 14288. In some embodiments, the siRNA comprises 14167, 14169, 14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236, 14237, 14238 8, one or more of the internucleoside linkages and / or nucleoside modifications of the antisense strand of 14240, 14242, 14247, 14248, 14249, 14250, 14251, 14252, 14254, 14257, 14259, 14264, 14269, 14270, 14271, 14275, 14278, 14279, 14280, 14281, 14282, 14283, 14284, 14285, 14286, 14287 or 14288.In some embodiments, the siRNA comprises 14167, 14169, 14170, 14172, 14174, 14175, 14176, 14177, 14179, 14181, 14182, 14183, 14188, 14190, 14204, 14205, 14207, 14209, 14210, 14212, 14213, 14215, 14223, 14230, 14234, 14235, 14236, 14237, 14238, 14240 14284, 14285, 14286, 14287, or 14288. In some embodiments, the siRNA is unmodified.

[0072] The siRNA may comprise an unmodified form of the sense strand sequence of an siRNA that reduces ANGPTL mRNA measurements by 10% or more relative to a control in Table 5 or Table 6. In some embodiments, the siRNA comprises SEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1155, 1156, 1157, 1158, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185 157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840, or 1842, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand sequence of any one of SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1 157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840, or 1842, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 50 9, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149 , 1151, 1154, 1157, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842.The siRNA may comprise SEQ ID NO: 32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 11 57, 1165, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of any one of SEQ ID NO:32, 33, 35, 36, 121, 280, 282, 289, 290, 292, 321, 323, 326, 332, 334, 484, 509, 519, 565, 570, 571, 620, 637, 640, 759, 834, 876, 1001, 1133, 1134, 1137, 1149, 1151, 1154, 1157, 116 5, 1166, 1171, 1172, 1248, 1249, 1285, 1338, 1348, 1430, 1489, 1490, 1564, 1580, 1581, 1589, 1597, 1611, 1702, 1840 or 1842, and a modification pattern described herein (e.g., modification pattern 1S, 2S, 3S, 4S, 5S or 6S).

[0073] The siRNA may comprise an unmodified form of the antisense strand sequence of an siRNA that reduces ANGPTL mRNA measurements by 10% or more relative to a control in Table 5 or Table 6. In some embodiments, the siRNA comprises SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3 003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the antisense strand sequence of any one of SEQ ID NO: NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2 338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3 003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the siRNA comprises SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987 , 2988, 2991, 3003, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696. The siRNA may comprise the antisense sequence of any one of SEQ ID NO:1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 23 38, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 30 03, 3005, 3008, 3011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, and one or more internucleoside linkages and / or one or more nucleoside modifications.The siRNA may comprise SEQ ID NO: 1886, 1887, 1889, 1890, 1975, 2134, 2136, 2143, 2144, 2146, 2175, 2177, 2180, 2186, 2188, 2338, 2363, 2373, 2419, 2424, 2425, 2474, 2491, 2494, 2613, 2688, 2730, 2855, 2987, 2988, 2991, 3003, 3005, 3008, 3010, 3011, 3013, 3014, 3015, 3016, 3017, 3018, 3019, 3020, 3021, 3022, 3023, 3024, 3025, 3026, 3027, 3028, 3029, 3030, 3031 011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, and a modification pattern described herein (e.g., modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS).

[0074] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 7, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 7, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 7. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 7. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 7. In some embodiments, the siRNA is unmodified.

[0075] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 8, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 8, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 8. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 8. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 8. In some embodiments, the siRNA is unmodified.

[0076] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 10, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 10, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 10. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 10. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 10. In some embodiments, the siRNA is unmodified.

[0077] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 15, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 15, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 15. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 15. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 15. In some embodiments, the siRNA is unmodified.

[0078] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 16, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 16, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 16. In some embodiments, the siRNA comprises one or more of the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 16. In some embodiments, the siRNA comprises the internucleoside linkages and / or nucleoside modifications of the siRNA in Table 16. In some embodiments, the siRNA is unmodified.

[0079] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13970-13973. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13970-13973. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13970-13973, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13970-13973, and a modification pattern described herein (e.g., modification pattern 1S, 2S, 3S, 4S, 5S, or 6S). The sense strand may comprise an overhang (e.g., 2 nucleotide overhangs, such as 2 uracil nucleotides).

[0080] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13978-13981. In some embodiments, the antisense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13978-13981, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13978-13981. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13978-13981, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13978-13981, and a modification pattern described herein (e.g., modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS). The antisense strand may comprise an overhang (eg, a 2 nucleotide overhang, such as 2 uracil nucleotides).

[0081] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13974-13977. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13974-13977, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13974-13977. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13974-13977, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13974-13977, and a modification pattern described herein (e.g., modification pattern 1S, 2S, 3S, 4S, 5S, or 6S). The sense strand may comprise an overhang.

[0082] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 13982-13985. In some embodiments, the antisense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13982-13985, or an antisense strand sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 13982-13985. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13982-13985, and one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a sense strand sequence of any one of SEQ ID NOs: 13982-13985, and a modification pattern described herein (e.g., modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS). The antisense strand may comprise an overhang.

[0083] In some embodiments, the sense strand and / or antisense strand comprises a nucleoside sequence that is at least 85% identical to the sense strand and / or antisense strand of any one of EDT01062 to ETD01065, EDT01062.1 to ETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 to ETD01065.3, EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5, EDT01062.6 to ETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 to ETD01065.8. In some embodiments, the sense and / or antisense strand comprises the sense and / or antisense strand of any one of EDT01062 to ETD01065, EDT01062.1 to ETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 to ETD01065.3, EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5, EDT01062.6 to ETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 to ETD01065.8, or a sense and / or antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand and / or antisense strand comprises any one of EDT01062 to ETD01065, EDT01062.1 to ETD01065.1, EDT01062.2 to ETD01065.2, EDT01062.3 to ETD01065.3, EDT01062.4 to ETD01065.4, EDT01062.5 to ETD01065.5, EDT01062.6 to ETD01065.6, EDT01062.7 to ETD01065.7, or EDT01062.8 to ETD01065.8. The sense strand and / or antisense strand may comprise a GalNAc ligand. The sense strand and / or antisense strand may not comprise any GalNAc ligand.

[0084] The sense strand may comprise a nucleoside sequence of SEQ ID NO: 13973 or a derivative thereof. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13973. The sense strand comprising a nucleoside sequence of SEQ ID NO: 13973 or a derivative thereof may include a sense strand comprising a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13973. In some embodiments, the sense strand comprises a nucleoside sequence of SEQ ID NO: 13973, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. The sense strand comprising a nucleoside sequence of a derivative of SEQ ID NO: 13973 may include a sense strand comprising a nucleoside sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of SEQ ID NO: 13973. The sense strand sequence may consist of the nucleotide sequence of SEQ ID NO: 13973. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise an overhang of 2 nucleotides. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 1S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 2S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 3S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 4S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 5S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13973 or its derivatives may comprise a modification pattern 6S.

[0085] The sense strand may comprise a nucleoside sequence of SEQ ID NO: 13977 or a derivative thereof. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13977. The sense strand comprising a nucleoside sequence of SEQ ID NO: 13977 or a derivative thereof may include a sense strand comprising a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13977. In some embodiments, the sense strand comprises a nucleoside sequence of SEQ ID NO: 13977, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. The sense strand comprising a nucleoside sequence of a derivative of SEQ ID NO: 13977 may include a sense strand comprising a nucleoside sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of SEQ ID NO: 13977. The sense strand sequence may consist of the nucleotide sequence of SEQ ID NO: 13977. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise an overhang of 2 nucleotides. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 1S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 2S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 3S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 4S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 5S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise modification pattern 6S.

[0086] The antisense strand may comprise a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof. In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13981. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may include an antisense strand comprising a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13981. In some embodiments, the antisense strand comprises a nucleoside sequence of SEQ ID NO: 13981, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. The antisense strand comprising a nucleoside sequence of a derivative of SEQ ID NO: 13981 may include an antisense strand comprising a nucleoside sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence of SEQ ID NO: 13981. The antisense strand sequence may consist of the nucleotide sequence of SEQ ID NO: 13981. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise an overhang of 2 nucleotides. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 1AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 2AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 3AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 4AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 5AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivatives may comprise a modification pattern 6AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivative may comprise the modification pattern 7AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivative may comprise the modification pattern 8AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13981 or its derivative may comprise the modification pattern 9AS.

[0087] The antisense strand may comprise a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof. In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13985. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may include an antisense strand comprising a nucleoside sequence that is at least 85% identical to SEQ ID NO: 13985. In some embodiments, the antisense strand comprises a nucleoside sequence of SEQ ID NO: 13985, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. The antisense strand comprising a nucleoside sequence of a derivative of SEQ ID NO: 13985 may include an antisense strand comprising a nucleoside sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence of SEQ ID NO: 13985. The antisense strand sequence may consist of the nucleotide sequence of SEQ ID NO: 13985. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise an overhang of 2 nucleotides. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 1AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 2AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 3AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 4AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 5AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivatives may comprise a modification pattern 6AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivative may comprise the modification pattern 7AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivative may comprise the modification pattern 8AS. The antisense strand comprising the nucleoside sequence of SEQ ID NO: 13985 or its derivative may comprise the modification pattern 9AS.

[0088] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 14006-14011. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 14006-14011, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 14006-14011. The sense strand may comprise a GalNAc ligand. In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to any one of SEQ ID NOs: 14158-14166. In some embodiments, the antisense strand comprises a nucleoside sequence of any one of SEQ ID NOs: 14158-14166, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 14158-14166. The antisense strand may comprise a GalNAc ligand.

[0089] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13970 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13970 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13970. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13978 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13978 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13978. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0090] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13971 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13971 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13971. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13979 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13979 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13979. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0091] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13972 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13972 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13972. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13980 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13980 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13980. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0092] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13973 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13973 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13973. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13981 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13981 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13981. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0093] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1285 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1285 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1285. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3139 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3139 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3139. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0094] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1580 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1580 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 1580. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3434 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3434 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 3434. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0095] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13974 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13974 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13974. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13982 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13982 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13982. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0096] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13975 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13975 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13975. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13983 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13983 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13983. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0097] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13976 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13976 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13976. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13984 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13984 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13984. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0098] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13977 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13977 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13977. In some embodiments, the sense strand comprises one or more internucleoside linkages and / or nucleoside modifications. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13985 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13985 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13985. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0099] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a seed region that is different from the seed region of a human miRNA. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a seed region that is different from the seed region of a human miRNA. In some embodiments, the siRNA cross-reacts with non-human primate (NHP) ANGPTL4 mRNA. For example, the antisense strand may bind to or be complementary to NHP ANGPTL4 mRNA.

[0100] B.ASO

[0101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0102] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO) that is about 12-30 nucleosides in length and comprises a nucleoside sequence that is complementary to about 12-30 contiguous nucleosides of a full-length human ANGPTL4 mRNA sequence, such as SEQ ID NO: 13935; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0103] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an ASO that is about 12-30 nucleosides in length and comprises a nucleoside sequence that is complementary to about 12-30 contiguous nucleosides of a full-length human ANGPTL4 mRNA sequence, such as SEQ ID NO: 13936; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0104] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an ASO comprising a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934. In some embodiments, the ASO comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the ASO comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.

[0105] C. Modification Mode

[0106] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises an alkylphosphonate, a phosphorothioate, a methylphosphonate, a phosphorodithioate, an alkylphosphonothioate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamidate, or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. Benefits of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics.

[0107] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, In some embodiments, the present invention comprises 1 modified internucleoside linkages, 12 modified internucleoside linkages, 13 modified internucleoside linkages, 14 modified internucleoside linkages, 15 modified internucleoside linkages, 16 modified internucleoside linkages, 17 modified internucleoside linkages, 18 modified internucleoside linkages, 19 modified internucleoside linkages, or 20 modified internucleoside linkages.

[0108] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises an HLA. In some embodiments, the modified nucleoside comprises a CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl. In some embodiments, the modified nucleoside comprises a 2'-fluoro. In some embodiments, the modified nucleoside comprises a 2'-deoxy. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2'-fluoro modified nucleosides. In some embodiments, the modified nucleosides include 2'O-alkyl modified nucleosides.Benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0109] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 modified nucleosides, or a range of nucleosides defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0110] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenyl, docosahexaenoyl, myristyl, palmitylstearyl, or alpha-tocopherol, or a combination thereof.

[0111] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. A "GalNAc ligand" can refer to a ligand of an asialoglycoprotein receptor (e.g., on hepatocytes) that comprises one or more GalNAc moieties. A GalNAc ligand can bind to an asialoglycoprotein receptor (e.g., on hepatocytes). A GalNAc ligand can comprise one or more GalNAc moieties. Examples of GalNAc moieties include GalNAc attached to a linker. A GalNAc ligand can comprise three GalNAc moieties. A GalNAc ligand can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more GalNAc moieties.

[0112] The GalNAc ligand can be conjugated to the oligonucleotide. The GalNAc ligand can be conjugated to the 5' end of the oligonucleotide. The GalNAc ligand can be conjugated to the 3' end of the oligonucleotide. The first GalNAc ligand can be conjugated to the 5' end of the oligonucleotide, and the second GalNAc ligand can be conjugated to the 3' end of the oligonucleotide. The GalNAc ligand can be conjugated to the 3' or 5' end of the ASO. The GalNAc ligand can be conjugated to the 3' or 5' end of the sense strand of the siRNA. The GalNAc ligand can be conjugated to the 3' end of the sense strand of the siRNA. The GalNAc ligand can be conjugated to the 5' end of the sense strand of the siRNA. The GalNAc ligand can be conjugated to the 3' or 5' end of the antisense strand of the siRNA. The GalNAc ligand can be conjugated to the 3' end of the antisense strand of the siRNA. The GalNAc ligand can be conjugated to the 5' end of the antisense strand of the siRNA. The first GalNAc ligand can be conjugated to the sense strand of the siRNA, and the second GalNAc ligand can be conjugated to the antisense strand of the siRNA.

[0113] 1. siRNA modification patterns

[0114] In some embodiments, the sense strand comprises 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, or 29 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the foregoing integers. In some embodiments, the sense strand comprises 1-11 modified internucleoside linkages. In some embodiments, the sense strand comprises 2-6 modified internucleoside linkages. In some embodiments, the sense strand comprises 5 modified internucleoside linkages. In some embodiments, the sense strand comprises 4 modified internucleoside linkages.

[0115] In some embodiments, the antisense strand comprises 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, or 29 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned integers. In some embodiments, the antisense strand comprises 1-11 modified internucleoside linkages. In some embodiments, the antisense strand comprises 2-6 modified internucleoside linkages. In some embodiments, the antisense strand comprises 5 modified internucleoside linkages. In some embodiments, the antisense strand comprises 4 modified internucleoside linkages.

[0116] In some embodiments, the sense strand comprises 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, or 30 modified nucleosides, or a range of modified nucleosides defined by any two of the aforementioned integers. In some embodiments, the sense strand comprises 12-19 modified nucleosides. In some embodiments, the sense strand comprises 12-21 modified nucleosides. In some embodiments, the sense strand comprises 19 modified nucleosides. In some embodiments, the sense strand comprises 21 modified nucleosides.

[0117] In some embodiments, the antisense strand comprises 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 or 30 modified nucleosides, or a range of modified nucleosides defined by any two of the aforementioned integers. In some embodiments, the antisense strand comprises 12-19 modified nucleosides. In some embodiments, the antisense strand comprises 12-21 modified nucleosides. In some embodiments, the antisense strand comprises 19 modified nucleosides. In some embodiments, the antisense strand comprises 21 modified nucleosides.

[0118] In some embodiments, the sense strand or antisense strand further comprises at least two additional nucleosides attached to the 3' end of the sense strand or antisense strand. In some embodiments, the sense strand or antisense strand comprises two additional nucleosides attached to the 3' end of the sense strand or antisense strand. The additional nucleosides as part of the sense strand may or may not be complementary to the ANGPTL4 mRNA. The additional nucleosides of the antisense strand may include uracil. Both additional nucleosides of the antisense strand may include uracil.

[0119] In some embodiments, the sense strand or sense strand further comprises at least two additional nucleosides attached to the 3' end of the sense strand or antisense strand. In some embodiments, the sense strand or sense strand comprises two additional nucleosides attached to the 3' end of the sense strand or antisense strand. The additional nucleosides of the sense strand can include uracil. The two additional nucleosides of the sense strand can both include uracil.

[0120] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5'-NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13954), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 13955), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 13956), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 4S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3' (SEQ ID NO: 13957), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N includes one or more nucleosides. In some embodiments, the sense strand comprises a modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsnN-3' (SEQ ID NO: 13958), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N includes one or more nucleosides. In some embodiments, the sense strand comprises a modification pattern 6S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13959), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N includes one or more nucleosides. Any of modification patterns 1S-6S can include a GalNAc ligand attached to the 3' end. Any of the modification patterns 1S-6S may include a GalNAc ligand attached to the 5' end.

[0121] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3' (SEQ ID NO: 13960), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'-nsNfsnnnNfnNfnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13961), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13962), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13963), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 5AS: 5'-nsNfsnnnNfnNfnnnnnfnNfnnnsnsn-3' (SEQ ID NO: 13964), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 6AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 13965), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 7AS: 5'-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13966), wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises modification pattern 8AS: 5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3' (SEQ ID NO: 13967), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3' (SEQ ID NO: 13968), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. Any of modification patterns 1AS-9AS can include a GalNAc ligand attached to the 3' end. Any of modification patterns 1AS-9AS can include a GalNAc ligand attached to the 5' end.

[0122] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern of 1S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 2S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 3S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 4S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 5S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 6S and the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the antisense strand comprises a modification pattern of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, either the sense strand or the antisense strand comprises a modification pattern of AS01.

[0123] Any combination of sense and antisense modification patterns can be used. In some embodiments, the sense strand comprises modification pattern 1S and the antisense strand comprises modification pattern 1AS. In some embodiments, the sense strand comprises modification pattern 2S and the antisense strand comprises modification pattern 2AS. In some embodiments, the sense strand comprises modification pattern 2S and the antisense strand comprises modification pattern 3AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 1AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 4AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 5AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 6AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 7AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 8AS. In some embodiments, the sense strand comprises modification pattern 6S and the antisense strand comprises modification pattern 1AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 4AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 5AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 6AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 7AS. In some embodiments, the sense strand comprises the modification pattern 6S and the antisense strand comprises the modification pattern 8AS.

[0124] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 1S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and a modification pattern of 1S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and a modification pattern of 1S.

[0125] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 2S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and a modification pattern of 2S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and a modification pattern of 2S.

[0126] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 3S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and a modification pattern of 3S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and a modification pattern of 3S.

[0127] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 4S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; and a modification pattern of 4S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern of 4S.

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 5S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and a modification pattern of 5S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and a modification pattern of 5S.

[0129] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern of 6S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and a modification pattern of 6S. In some embodiments, the sense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and a modification pattern of 6S.

[0130] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 1AS.

[0131] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 2AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 2AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 2AS.

[0132] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 3AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; and a modification pattern 3AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern 3AS.

[0133] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and the modification pattern 4AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; and the modification pattern 4AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions; and the modification pattern 4AS.

[0134] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 5AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; and a modification pattern 5AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern 5AS.

[0135] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and the modification pattern 6AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof; and the modification pattern 6AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof; and the modification pattern 6AS.

[0136] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and the modification pattern 7AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof; and the modification pattern 7AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof; and the modification pattern 7AS.

[0137] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and the modification pattern 8AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions, and the modification pattern 8AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions, and the modification pattern 8AS.

[0138] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 9AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 9AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof, and a modification pattern 9AS.

[0139] In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 1S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 2S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 3S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 4S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 5S. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 2-base 3' overhang), and a modification pattern 6S. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 and an overhang (such as a 2-base 3' overhang) and modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 and an overhang (such as a 2-base 3' overhang) and modification pattern 2AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 and an overhang (such as a 2-base 3' overhang) and modification pattern 3AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985 and an overhang (such as a 2-base 3' overhang) and the modification pattern 4AS.In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang (such as a 2-base 3' overhang), and a modification pattern 5AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang (such as a 2-base 3' overhang), and a modification pattern 6AS. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985, and an overhang (such as a 2-base 3' overhang), and a modification pattern 7AS. In some embodiments, the antisense strand comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 8AS, and the nucleoside sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985. In some embodiments, the antisense strand comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 9AS, and the nucleoside sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985. In some embodiments, the overhang comprises one or more uridine nucleosides. In some embodiments, the one or more uridine nucleosides of the overhang are connected to another nucleoside at the 3' end via a phosphorothioate linkage. In some embodiments, the overhang comprises one uridine nucleoside. In some embodiments, the overhang comprises two uridine nucleosides.

[0140] Some embodiments include a composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide sequence of SEQ ID NO: 759, 1285, 1580, or 1840 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of SEQ ID NO: 759, 1285, 1580, or 1840 wherein at least one internucleoside linkage is modified and at least one base is modified, and wherein the antisense strand comprises the oligonucleotide sequence of SEQ ID NO: 2613, 3139, 3434, or 3694 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising SEQ ID NO: 2613, 3139, 3434, or 3694 wherein at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having one or two nucleoside substitutions, additions or deletions of NO: 2613, 3139, 3434 or 3694.

[0141] Some embodiments include a composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide sequence of any one of SEQ ID NOs: 13970-13973 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any one of SEQ ID NOs: 13970-13973 wherein at least one internucleoside linkage is modified and at least one base is modified, and wherein the antisense strand comprises the oligonucleotide sequence of any one of SEQ ID NOs: 13978-13981 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having one or two nucleoside substitutions, additions or deletions of any one of NOs: 13978-13981.

[0142] Some embodiments include a composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide sequence of any one of SEQ ID NOs: 13974-13977 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any one of SEQ ID NOs: 13974-13977 wherein at least one internucleoside linkage is modified and at least one base is modified, and wherein the antisense strand comprises the oligonucleotide sequence of any one of SEQ ID NOs: 13982-13985 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having 1 or 2 nucleoside substitutions, additions or deletions of any one of NOs: 13982-13985.

[0143] Some embodiments include a composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide sequence of any one of SEQ ID NOs: 13990-14005 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any one of SEQ ID NOs: 13990-14005 wherein at least one internucleoside linkage is modified and at least one base is modified, and wherein the antisense strand comprises an oligonucleotide sequence of any one of SEQ ID NOs: 14134-14157 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having one or two nucleoside substitutions, additions or deletions of any one of NOs: 14134-14157.

[0144] Some embodiments include a composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide sequence of any one of SEQ ID NOs: 1-1854 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any one of SEQ ID NOs: 1-1854 wherein at least one internucleoside linkage is modified and at least one base is modified, and wherein the antisense strand comprises an oligonucleotide sequence of any one of SEQ ID NOs: 1855-3708 wherein at least one internucleoside linkage is modified and at least one base is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any one of SEQ ID NOs: 1855-3708 wherein at least one internucleoside linkage is modified and at least one base is modified.

[0145] 2. ASO modification pattern

[0146] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises the modification pattern ASO1: 5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3', wherein "dN" is any deoxynucleotide, "n" is a 2'O-methyl or 2'O-methoxyethyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the ASO comprises the modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the ASO comprises DNA.

[0147] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934, and a modification pattern ASO1. In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof; and a modification pattern ASO1. In some embodiments, the ASO comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3709-13934; or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof; and a modification pattern ASO1.

[0148] ASO1 modification pattern ASO1 may comprise a GalNAc ligand attached to the 3' end. ASO1 modification pattern ASO1 may comprise a GalNAc ligand attached to the 5' end.

[0149] D. Preparation

[0150] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0151] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises liposomes. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogels, or combinations thereof.

[0152] II. Methods and Uses

[0153] Disclosed herein, in some embodiments, are methods of administering the compositions described herein to a subject.Some embodiments relate to using the compositions described herein, such as administering the compositions to a subject.

[0154] Some embodiments relate to methods of treating a condition in a subject in need thereof. Some embodiments relate to the use of the compositions described herein in methods of treatment. Some embodiments comprise administering a composition described herein to a subject suffering from a condition. In some embodiments, the administration treats the condition in the subject. In some embodiments, the composition treats the condition in the subject.

[0155] In some embodiments, treatment includes preventing, inhibiting, or reversing a condition in a subject. Some embodiments relate to the use of a composition as described herein in a method for preventing, inhibiting, or reversing a condition. Some embodiments relate to methods for preventing, inhibiting, or reversing a condition in a subject in need thereof. Some embodiments comprise administering a composition as described herein to a subject having a condition. In some embodiments, administration prevents, inhibits, or reverses a condition in a subject. In some embodiments, the composition prevents, inhibits, or reverses a condition in a subject.

[0156] Some embodiments relate to methods of preventing a condition in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of preventing a condition. Some embodiments comprise administering a composition described herein to a subject having a condition. In some embodiments, the administration prevents the condition in a subject. In some embodiments, the composition prevents the condition in a subject.

[0157] Some embodiments relate to methods of inhibiting a condition in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of inhibiting a condition. Some embodiments comprise administering a composition described herein to a subject having a condition. In some embodiments, the administration inhibits the condition in the subject. In some embodiments, the composition inhibits the condition in the subject.

[0158] Some embodiments relate to methods of reversing a condition in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of reversing a condition. Some embodiments comprise administering a composition described herein to a subject having a condition. In some embodiments, administration reverses the condition in the subject. In some embodiments, the composition reverses the condition in the subject.

[0159] A. Symptoms

[0160] Some embodiments of the methods described herein include treating a condition in a subject in need thereof. In some embodiments, the condition is a metabolic condition. Examples of metabolic conditions include hyperlipidemia (e.g., hypertriglyceridemia) and diabetes (e.g., type 2 diabetes). In some embodiments, the metabolic condition includes hyperlipidemia. In some embodiments, the metabolic condition includes hypertriglyceridemia. In some embodiments, the metabolic condition includes familial chylomicronemia. In some embodiments, the metabolic condition includes hypertriglyceridemia in the context of familial chylomicronemia. In some embodiments, the metabolic condition includes pancreatitis. In some embodiments, the metabolic condition includes acute pancreatitis. In some embodiments, the metabolic condition includes hypertriglyceridemia and associated acute pancreatitis. In some embodiments, the metabolic condition includes diabetes. In some embodiments, the metabolic condition includes type 2 diabetes. Some embodiments include a method of treating a metabolic condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL4.

[0161] In some embodiments, the condition is a cardiometabolic condition, such as a cardiovascular condition or a metabolic condition. In some embodiments, the condition is a cardiovascular condition. Examples of cardiovascular conditions include heart disease, myocardial infarction, angina (e.g., angina pectoris), and atherosclerosis. In some embodiments, cardiovascular conditions include heart disease. In some embodiments, cardiovascular conditions include myocardial infarction. In some embodiments, cardiovascular conditions include angina pectoris. In some embodiments, cardiovascular conditions include atherosclerosis. Some embodiments include a method of treating a cardiovascular condition in a subject in need thereof, comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL4.

[0162] B. Object

[0163] Some embodiments of the methods described herein include treatment of a subject. Examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cow. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cow, rodent, mouse, rat, primate, or monkey. In some embodiments, the subject is a human.

[0164] In some embodiments, the subject has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or higher, or a range defined by any two of the aforementioned integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or higher. In some embodiments, the subject has a BMI of 25-29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or higher. In some embodiments, the subject has a BMI of 30-39. In some embodiments, the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 25-50.

[0165] In some embodiments, the subject is ≥90 years old. In some embodiments, the subject is ≥85 years old. In some embodiments, the subject is ≥80 years old. In some embodiments, the subject is ≥70 years old. In some embodiments, the subject is ≥60 years old. In some embodiments, the subject is ≥50 years old. In some embodiments, the subject is ≥40 years old. In some embodiments, the subject is ≥30 years old. In some embodiments, the subject is ≥20 years old. In some embodiments, the subject is ≥10 years old. In some embodiments, the subject is ≥1 year old. In some embodiments, the subject is ≥0 years old.

[0166] In some embodiments, the subject is ≤ 100 years old. In some embodiments, the subject is ≤ 90 years old. In some embodiments, the subject is ≤ 85 years old. In some embodiments, the subject is ≤ 80 years old. In some embodiments, the subject is ≤ 70 years old. In some embodiments, the subject is ≤ 60 years old. In some embodiments, the subject is ≤ 50 years old. In some embodiments, the subject is ≤ 40 years old. In some embodiments, the subject is ≤ 30 years old. In some embodiments, the subject is ≤ 20 years old. In some embodiments, the subject is ≤ 10 years old. In some embodiments, the subject is ≤ 1 year old.

[0167] In some embodiments, the subject is between 0 and 100 years old. In some embodiments, the subject is between 20 and 90 years old. In some embodiments, the subject is between 30 and 80 years old. In some embodiments, the subject is between 40 and 75 years old. In some embodiments, the subject is between 50 and 70 years old. In some embodiments, the subject is between 40 and 85 years old.

[0168] C. Baseline measurements

[0169] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from a subject prior to treatment of the subject.

[0170] In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay on a sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, or a fluorometric assay. In some embodiments, the baseline measurement is obtained by PCR.

[0171] In some embodiments, the baseline measurement is a baseline triglyceride measurement. In some embodiments, the baseline triglyceride measurement is a baseline triglyceride concentration (e.g., mg / dL). In some embodiments, the baseline triglyceride measurement is a baseline circulating triglyceride measurement.

[0172] In some embodiments, the baseline triglyceride measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0173] In some embodiments, the baseline measurement is a baseline cholesterol measurement. In some embodiments, the baseline cholesterol measurement is a baseline cholesterol concentration. In some embodiments, the baseline cholesterol concentration is a baseline total cholesterol concentration. In some embodiments, the baseline cholesterol measurement is a baseline circulating cholesterol measurement. In some embodiments, the baseline cholesterol measurement is a baseline low-density lipoprotein (LDL) measurement. In some embodiments, the baseline cholesterol measurement is a baseline very low-density lipoprotein (VLDL) measurement. In some embodiments, the baseline cholesterol measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0174] In some embodiments, the baseline measurement is a baseline HDL measurement. In some embodiments, the baseline HDL measurement is a baseline HDL concentration. In some embodiments, the baseline HDL measurement is expressed relative to a baseline total cholesterol measurement. In some embodiments, the baseline HDL measurement is a baseline circulating HDL measurement. In some embodiments, the baseline HDL measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0175] In some embodiments, the baseline measurement is a baseline glucose measurement. In some embodiments, the baseline glucose measurement is a baseline glucose concentration (e.g., mg / dL). In some embodiments, the baseline glucose measurement comprises a baseline glucose concentration. In some embodiments, the baseline glucose measurement is a baseline circulating glucose measurement. In some embodiments, the baseline glucose measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay. In some embodiments, the baseline glucose measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0176] In some embodiments, baseline glucose measurement includes a baseline glucose tolerance test. In some embodiments, the baseline glucose tolerance test includes administering glucose to the object, and then obtaining multiple baseline glucose measurements over time after administering glucose to the object. In some embodiments, glucose is administered orally. In some embodiments, glucose is administered by injection. In some embodiments, multiple baseline glucose measurements are integrated into baseline glucose area under the curve (AUC) measurement. In some embodiments, a baseline glucose tolerance test is performed on an object in a fasting state (such as after an overnight fast). In some embodiments, baseline glucose measurement includes the baseline glucose measurement in addition to the baseline glucose tolerance test.

[0177] In some embodiments, the baseline measurement value is a baseline insulin measurement value. In some embodiments, the baseline insulin measurement value is a baseline insulin sensitivity measurement value. In some embodiments, the baseline insulin sensitivity measurement value is obtained using a glucose clamp technique (such as a hyperinsulinemic euglycemic clamp). In some embodiments, the baseline insulin measurement value is a baseline insulin concentration. In some embodiments, the baseline insulin measurement value includes a baseline insulin concentration. In some embodiments, the baseline insulin measurement value is a baseline circulating insulin measurement value. In some embodiments, the baseline insulin measurement value is obtained by an assay such as an immunoassay (e.g., ELISA or immunoblot), a colorimetric assay, or a fluorometric assay. In some embodiments, the baseline insulin sensitivity measurement includes a baseline glucose tolerance test. In some embodiments, the baseline insulin sensitivity measurement includes a baseline insulin sensitivity measurement other than a baseline glucose tolerance test.

[0178] In some embodiments, baseline insulin measurement includes a baseline insulin response test. In some embodiments, the baseline insulin response test includes administering glucose to the object, then obtaining multiple baseline insulin measurements over time after administering glucose to the object. In some embodiments, glucose is administered orally. In some embodiments, glucose is administered by injection. In some embodiments, multiple baseline insulin measurements are integrated into a baseline insulin AUC measurement. In some embodiments, a baseline insulin response test is performed on an object in a fasted state (such as after an overnight fast).

[0179] In some embodiments, baseline insulin measurement includes a baseline glucose reaction test. In some embodiments, the baseline glucose reaction test includes administering insulin to the object, then obtaining multiple baseline glucose measurements over time after administering insulin to the object. In some embodiments, insulin is administered by injection. In some embodiments, multiple baseline glucose measurements are integrated into a baseline glucose AUC measurement. In some embodiments, multiple baseline glucose measurements are obtained with a blood glucose meter. In some embodiments, glucose reaction tests are carried out on the object in a fasting state (such as after overnight fasting). In some embodiments, the glucose reaction test is carried out on the object after administering food, beverage or glucose to the object.

[0180] In some embodiments, the baseline measurement is a baseline ANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4 protein measurement comprises a baseline ANGPTL4 protein level. In some embodiments, the baseline ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per sample weight. In some embodiments, the baseline ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per sample volume. In some embodiments, the baseline ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per total protein in the sample. In some embodiments, the baseline ANGPTL4 protein measurement is a baseline cellular (e.g., hepatocyte) ANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4 protein measurement is a baseline tissue (e.g., liver tissue) ANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4 protein measurement is a baseline circulating ANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0181] In some embodiments, the baseline measurement is a baseline ANGPTL4 mRNA measurement. In some embodiments, the baseline ANGPTL4 mRNA measurement comprises a baseline ANGPTL4 mRNA level. In some embodiments, the baseline ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per sample weight. In some embodiments, the baseline ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per sample volume. In some embodiments, the baseline ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total mRNA in the sample. In some embodiments, the baseline ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total nucleic acid in the sample. In some embodiments, the baseline ANGPTL4 mRNA level is expressed relative to the level of another mRNA in the sample, such as the mRNA level of a housekeeping gene. In some embodiments, the baseline ANGPTL4 mRNA measurement is obtained by an assay, such as a polymerase chain reaction (PCR) assay. In some embodiments, PCR comprises quantitative PCR (qPCR). In some embodiments, PCR comprises reverse transcription of ANGPTL4 mRNA.

[0182] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained in a sample obtained from a subject. In some embodiments, a sample is obtained from a subject prior to administering a composition as described herein or treating a subject with a composition as described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from a subject prior to administering the composition to the subject. In some embodiments, a sample is obtained from a subject in a fasting state. In some embodiments, a sample is obtained from a subject after an overnight fasting period. In some embodiments, a sample is obtained from a subject in a fed state.

[0183] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. For example, a baseline triglyceride 33 measurement, a baseline cholesterol measurement, a baseline HDL measurement, a baseline glucose measurement, a baseline insulin measurement, or a baseline ANGPTL4 protein measurement can be obtained in a serum sample from a patient.

[0184] In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample comprises liver tissue. In some embodiments, the sample is a liver sample. In some embodiments, the sample comprises adipose tissue. In some embodiments, the sample is an adipose sample. In some embodiments, the sample comprises pancreatic tissue. In some embodiments, the sample comprises a pancreatic sample. For example, a baseline ANGPTL4 mRNA measurement or a baseline ANGPTL4 protein measurement can be obtained in a liver or adipose sample from a patient. In some embodiments, the sample comprises intestinal tissue, such as small intestinal tissue. In some embodiments, the sample is a small intestinal sample. In some embodiments, the sample comprises lymph node tissue, such as mesenteric lymph node tissue. In some embodiments, the sample is a mesenteric lymph node sample. In some embodiments, the sample comprises cardiac tissue, such as ventricular or atrial tissue. In some embodiments, the sample is a cardiac sample. In some embodiments, the tissue sample comprises liver, adipose, small intestine, mesenteric lymph node, or cardiac tissue. In some embodiments, the tissue sample comprises brown adipose tissue, white adipose tissue, kidney tissue, or muscle tissue.

[0185] D. Effect

[0186] In some embodiments, the composition or administration of the composition affects a measurement such as a triglyceride measurement, a cholesterol measurement, an HDL measurement, a glucose measurement, an insulin measurement, an ANGPTL4 protein measurement (e.g., circulating or tissue ANGPTL4 protein level), or an ANGPTL4 mRNA measurement relative to a baseline measurement.

[0187] Some embodiments of the methods described herein include obtaining a measurement from a subject. For example, a measurement can be obtained from a subject after the subject has been treated. In some embodiments, after the composition is administered to the subject, a measurement is obtained from a second sample (such as a fluid or tissue sample as described herein) obtained from the subject. In some embodiments, the measurement is an indication that the condition has been treated.

[0188] In some embodiments, the measurement is obtained by an assay as described herein. For example, the assay can include an immunoassay, a colorimetric assay, a fluorescence assay, or a PCR assay.

[0189] In some embodiments, the measurements are obtained within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition. In some embodiments, the measurements are obtained after 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition.

[0190] In some embodiments, the measured value is a triglyceride measured value. In some embodiments, the triglyceride measured value is a triglyceride concentration (e.g., mg / dL). In some embodiments, the triglyceride measured value is a circulating triglyceride measured value. In some embodiments, the triglyceride measured value is obtained by a determination such as an immunoassay, a colorimetric determination, or a fluorometric determination.

[0191] In some embodiments, the composition reduces triglyceride measurements relative to baseline triglyceride measurements. In some embodiments, the composition reduces circulating triglycerides relative to baseline triglyceride measurements. In some embodiments, the reduced triglycerides are measured in a second sample obtained from the subject after the composition is administered to the subject.

[0192] In some embodiments, relative to baseline triglyceride measurement value, triglyceride measurement value reduces by about 2.5% or more, about 5% or more or about 7.5% or more. In some embodiments, relative to baseline triglyceride measurement value, triglyceride measurement value reduces by about 10% or more. In some embodiments, relative to baseline triglyceride measurement value, triglyceride measurement value reduces by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more or about 100%. In some embodiments, relative to baseline triglyceride measurement value, triglyceride measurement value reduces by no more than about 2.5%, no more than about 5% or no more than about 7.5%. In some embodiments, relative to baseline triglyceride measurement value, triglyceride measurement value reduces by no more than about 10%. In some embodiments, the triglyceride measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline triglyceride measurement. In some embodiments, the triglyceride measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range defined by any two of the foregoing percentages.

[0193] In some embodiments, the measured value is a cholesterol measured value. In some embodiments, the cholesterol measured value is a total cholesterol measured value. In some embodiments, the cholesterol measured value is a cholesterol concentration. In some embodiments, the cholesterol concentration is a total cholesterol concentration. In some embodiments, the cholesterol measured value is a circulating cholesterol measured value. In some embodiments, the cholesterol measured value is a low-density lipoprotein (LDL) measured value. In some embodiments, the cholesterol measured value is a very low-density lipoprotein (VLDL) measured value. In some embodiments, the cholesterol measured value is obtained by a determination such as an immunoassay, a colorimetric determination, or a fluorometric determination.

[0194] In some embodiments, the compositions reduce cholesterol measurements relative to baseline cholesterol measurements. In some embodiments, the compositions reduce circulating cholesterol relative to baseline cholesterol measurements. In some embodiments, after the compositions are administered to the subject, the reduced cholesterol is measured in a second sample obtained from the subject.

[0195] In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value reduces by about 2.5% or more, about 5% or more or about 7.5% or more. In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value reduces by about 10% or more. In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value reduces by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more or about 100%.

[0196] In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value has reduced and is no more than about 2.5%, is no more than about 5% or is no more than about 7.5%.In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value has reduced and is no more than about 10%.In some embodiments, relative to baseline cholesterol measured value, cholesterol measured value has reduced and is no more than about 20%, is no more than about 30%, is no more than about 40%, is no more than about 50%, is no more than about 60%, is no more than about 70%, is no more than about 80%, is no more than about 90% or is no more than about 100%.In some embodiments, cholesterol measured value has reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or by the scope of any two aforementioned percentage definitions.

[0197] In some embodiments, the measurement is an HDL measurement. In some embodiments, the HDL measurement is HDL concentration. In some embodiments, the HDL measurement is expressed relative to the total cholesterol measurement. In some embodiments, the HDL measurement is a circulating HDL measurement. In some embodiments, the HDL measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0198] In some embodiments, the composition reduces HDL measurements relative to baseline HDL measurements. In some embodiments, the composition increases circulating HDL relative to baseline HDL measurements. In some embodiments, the increased HDL is measured in a second sample obtained from the subject after the composition is administered to the subject.

[0199] In some embodiments, the HDL measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline HDL measurement. In some embodiments, the HDL measurement is increased by about 10% or more relative to the baseline HDL measurement. In some embodiments, the HDL measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more relative to the baseline HDL measurement. In some embodiments, the HDL measurement is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more relative to the baseline HDL measurement. In some embodiments, the HDL measurement value increases by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value increases by no more than about 10% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value increases by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value increases by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by any two of the foregoing percentages.

[0200] In some embodiments, the measured value is a glucose measured value. In some embodiments, the glucose measured value includes a glucose concentration (e.g., mg / dL). In some embodiments, the glucose measured value is a glucose concentration. In some embodiments, the glucose measured value is a circulating glucose measured value. In some embodiments, the glucose measured value is obtained by a measure such as an immunoassay, a colorimetric assay, or a fluorometric assay. In some embodiments, the glucose measured value is obtained using a glucometer.

[0201] In some embodiments, glucose measurement includes a glucose tolerance test. In some embodiments, the glucose tolerance test includes administering glucose to the object, then obtaining multiple glucose measurement values ​​over time after administering glucose to the object. In some embodiments, glucose is administered orally. In some embodiments, glucose is administered by injection. In some embodiments, multiple glucose measurement values ​​are integrated into glucose area under the curve (AUC) measurement value. In some embodiments, a glucose tolerance test is performed to the object in a fasting state (such as after an overnight fast). In some embodiments, glucose measurement includes the glucose measurement except the glucose tolerance test.

[0202] In some embodiments, the composition reduces glucose measurements relative to baseline glucose measurements. In some embodiments, the composition reduces circulating glucose relative to baseline glucose measurements. In some embodiments, after the composition is administered to the subject, the reduced glucose is measured in a second sample obtained from the subject. In some embodiments, the composition reduces one or more of the multiple glucose measurements of a glucose tolerance test relative to one or more of the multiple glucose measurements of a baseline glucose tolerance test. In some embodiments, the composition reduces glucose AUC measurements relative to baseline glucose AUC measurements.

[0203] In some embodiments, the glucose measurement value is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline glucose measurement value. In some embodiments, the glucose measurement value is reduced by about 10% or more relative to the baseline glucose measurement value. In some embodiments, the glucose measurement value is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to the baseline glucose measurement value.

[0204] In some embodiments, relative to baseline glucose measured value, glucose reduces and is no more than about 2.5%, no more than about 5% or no more than about 7.5%.In some embodiments, relative to baseline glucose measured value, glucose reduces and is no more than about 10%.In some embodiments, relative to baseline glucose measured value, glucose reduces and is no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90% or no more than about 100%.In some embodiments, glucose measured value reduces by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or the scope defined by any two aforementioned percentages.

[0205] In some embodiments, the measured value is an insulin measurement value. In some embodiments, the insulin measurement value is an insulin sensitivity measurement value. In some embodiments, the insulin sensitivity measurement value is obtained using a glucose clamp technique (such as a hyperinsulinemic euglycemic clamp). In some embodiments, the insulin measurement value includes insulin concentration. In some embodiments, the insulin measurement value is insulin concentration. In some embodiments, the insulin measurement value is a circulating insulin measurement value. In some embodiments, the insulin measurement value is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay. In some embodiments, the insulin sensitivity measurement includes a glucose tolerance test. In some embodiments, the insulin sensitivity measurement includes an insulin sensitivity measurement other than a glucose tolerance test.

[0206] In some embodiments, insulin measurement includes insulin response test. In some embodiments, insulin response test includes administering glucose to the object, then after administering glucose to the object, passes over time and obtains multiple insulin measured values. In some embodiments, glucose is administered orally. In some embodiments, glucose is administered by injection. In some embodiments, multiple insulin measured values ​​are integrated into insulin AUC measured value. In some embodiments, the object in fasting state (such as after overnight fasting) is carried out insulin response test.

[0207] In some embodiments, insulin measurement includes glucose reaction test. In some embodiments, glucose reaction test includes administering insulin to the object, then after administering insulin to the object, a plurality of glucose measured values ​​are obtained over time. In some embodiments, insulin is administered by injection. In some embodiments, a plurality of glucose measured values ​​are integrated into a glucose AUC measured value. In some embodiments, a plurality of glucose measured values ​​are measured with a blood glucose meter. In some embodiments, glucose reaction test is carried out to the object in a fasting state (such as after overnight fasting). In some embodiments, glucose reaction test is carried out to the object after administering food, beverage or glucose to the object.

[0208] In some embodiments, the composition increases insulin sensitivity relative to baseline insulin sensitivity measurements. In some embodiments, relative to baseline insulin sensitivity measurements, insulin sensitivity increases by about 2.5% or more, about 5% or more, or about 7.5% or more. In some embodiments, relative to baseline insulin sensitivity measurements, insulin sensitivity increases by about 10% or more. In some embodiments, relative to baseline insulin sensitivity measurements, insulin sensitivity increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more. In some embodiments, relative to baseline insulin sensitivity measurements, insulin sensitivity increases by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more. In some embodiments, insulin sensitivity is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to baseline insulin sensitivity measurements. In some embodiments, insulin sensitivity is increased by no more than about 10% relative to baseline insulin sensitivity measurements. In some embodiments, insulin sensitivity is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to baseline insulin sensitivity measurements. In some embodiments, insulin sensitivity is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% relative to baseline insulin sensitivity measurements. In some embodiments, insulin sensitivity is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by any two of the foregoing percentages.

[0209] In some embodiments, the compositions reduce insulin measurements relative to baseline insulin measurements. In some embodiments, the compositions reduce circulating insulin relative to baseline insulin measurements. In some embodiments, after the compositions are administered to the subject, the reduced insulin is measured in a second sample obtained from the subject. In some embodiments, the compositions reduce insulin AUC measurements relative to baseline insulin AUC measurements.

[0210] In some embodiments, the insulin measurement value is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline insulin measurement value. In some embodiments, the insulin measurement value is reduced by about 10% or more relative to the baseline insulin measurement value. In some embodiments, the insulin measurement value is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to the baseline insulin measurement value.

[0211] In some embodiments, relative to the baseline insulin measured value, insulin has reduced by no more than about 2.5%, no more than about 5% or no more than about 7.5%. In some embodiments, relative to the baseline insulin measured value, insulin has reduced by no more than about 10%. In some embodiments, relative to the baseline insulin measured value, insulin has reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90% or no more than about 100%. In some embodiments, the insulin measured value has reduced by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or the scope defined by any two aforementioned percentages.

[0212] In some embodiments, the measurement is an ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement comprises an ANGPTL4 protein level. In some embodiments, the ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per sample weight. In some embodiments, the ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per sample volume. In some embodiments, the ANGPTL4 protein level is expressed as mass or percentage of ANGPTL4 protein per total protein in the sample. In some embodiments, the ANGPTL4 protein measurement is a cell (e.g., hepatocyte) ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is a tissue (e.g., liver tissue) ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is a circulating ANGPTL4 protein measurement. In some embodiments, the baseline ANGPTL4 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorometric assay.

[0213] In some embodiments, the composition reduces ANGPTL4 protein measurements relative to baseline ANGPTL4 protein measurements. In some embodiments, the composition reduces circulating ANGPTL4 protein levels relative to baseline ANGPTL4 protein measurements. In some embodiments, the composition reduces tissue ANGPTL4 protein levels (such as liver tissue ANGPTL protein levels) relative to baseline ANGPTL4 protein measurements. In some embodiments, the composition reduces cellular ANGPTL4 protein levels (such as hepatocyte ANGPTL protein levels) relative to baseline ANGPTL4 protein measurements. In some embodiments, after administering the composition to the subject, the reduced ANGPTL4 protein level is measured in a second sample obtained from the subject.

[0214] In some embodiments, the ANGPTL4 protein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is reduced by about 10% or more relative to the baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to the baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is reduced by no more than about 10% relative to the baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to a baseline ANGPTL4 protein measurement. In some embodiments, the ANGPTL4 protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range defined by any two of the foregoing percentages.

[0215] In some embodiments, the measurement is an ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement comprises an ANGPTL4 mRNA level. In some embodiments, the ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per sample weight. In some embodiments, the ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per sample volume. In some embodiments, the ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total mRNA in the sample. In some embodiments, the ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total nucleic acid in the sample. In some embodiments, the ANGPTL4 mRNA level is expressed relative to the level of another mRNA in the sample, such as the mRNA level of a housekeeping gene. In some embodiments, the ANGPTL4 mRNA measurement is obtained by an assay, such as a PCR assay. In some embodiments, PCR comprises qPCR.

[0216] In some embodiments, PCR comprises reverse transcription of ANGPTL4 mRNA.

[0217] In some embodiments, the composition reduces ANGPTL4 mRNA measurements relative to baseline ANGPTL4 mRNA measurements. In some embodiments, after administering the composition to the subject, ANGPTL4 mRNA measurements are obtained in a second sample obtained from the subject. In some embodiments, the composition reduces ANGPTL4 mRNA levels relative to baseline ANGPTL4 mRNA levels. In some embodiments, after administering the composition to the subject, the reduced ANGPTL4 mRNA levels are measured in a second sample obtained from the subject. In some embodiments, the second sample is a liver sample. In some embodiments, the second sample is a fat sample.

[0218] In some embodiments, the ANGPTL4 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to a baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by about 10% or more relative to a baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to a baseline ANGPTL4 mRNA measurement.

[0219] In some embodiments, the ANGPTL4 mRNA measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to a baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by no more than about 10% relative to a baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to a baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range defined by any two of the foregoing percentages.

[0220] III. Definitions

[0221] Unless otherwise defined, all technical terms, symbols, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ease of reference, and such definitions included herein should not necessarily be construed to represent a substantial difference from what is generally understood in the art.

[0222] Throughout this application, various embodiments can be presented in the form of ranges. It should be understood that the description of ranges is merely for convenience and brevity, and should not be construed as a rigid limitation on the scope of the present disclosure. Therefore, the description of a range should be considered as having all possible sub-ranges disclosed and individual numerical values ​​within the scope. For example, a description of a range such as 1 to 6 should be considered as having individual numerical values ​​within the scope of the disclosure, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within this range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0223] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "sample" includes a plurality of samples, including mixtures thereof.

[0224] The terms "determine," "measure," "evaluate," "assess," "assay," and "analyze" are generally used interchangeably herein to refer to forms of measurement. The terms include determining whether an element is present (e.g., detecting). These terms can include quantitative, qualitative, or both quantitative and qualitative determinations. An assessment can be relative or absolute. In addition to determining whether something is present or absent based on context, "detecting the presence of" can also include determining the amount of something that is present.

[0225] The terms "subject" and "patient" are used interchangeably herein. A "subject" can be a biological entity containing expressed genetic material. A biological entity can be a plant, an animal, or a microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be a mammal. A mammal can be a human. A subject can be diagnosed or suspected of being at high risk for a disease. In some cases, a subject is not necessarily diagnosed or suspected of being at high risk for a disease.

[0226] As used herein, the term "about" a number refers to plus or minus 10% of the number. The term "about" a range refers to the range minus 10% of its lower limit and plus 10% of its upper limit.

[0227] As used herein, the term "treatment" or "treating" refers to a drug or other intervention regimen for obtaining a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, therapeutic benefits and / or preventive benefits. Therapeutic benefit can refer to eradicating or improving the underlying condition or its symptoms being treated. In addition, therapeutic benefit can be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition so that improvement is observed in the subject, although the subject may still be troubled by the underlying condition. Preventive effects include delaying, preventing or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing down, stopping or reversing the progress of a disease or condition, or any combination thereof. For preventive benefits, treatment can be performed on a subject at risk of developing a specific disease or on a subject reporting one or more physiological symptoms of a disease (even if a diagnosis of the disease may not yet have been made).

[0228] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0229] IV. Sequence Information

[0230] Some embodiments include one or more nucleic acid sequences in the following table:

[0231] Table 1. Sequence information

[0232]

[0233]

[0234] V. Implementation Plan

[0235] Some embodiments include one or more of the following:

[0236] 1. A composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and lowers circulating triglycerides when administered to a subject in an effective amount.

[0237] 2. The composition of embodiment 1, wherein triglycerides are reduced by about 10% or more as compared to before administration.

[0238] 3. A composition comprising an oligonucleotide that targets ANGPTL4 and that lowers circulating total cholesterol when administered to a subject in an amount effective to do so.

[0239] 4. The composition of embodiment 3, wherein the total cholesterol is reduced by about 10% or more as compared to before administration.

[0240] 5. A composition comprising an oligonucleotide that targets ANGPTL4 and increases circulating high-density lipoprotein (HDL) when administered to a subject in an effective amount.

[0241] 6. The composition of embodiment 5, wherein HDL is increased by about 10% or more as compared to before administration.

[0242] 7. A composition comprising an oligonucleotide that targets ANGPTL4 and lowers circulating glucose when administered to a subject in an effective amount.

[0243] 8. The composition of embodiment 7, wherein glucose is reduced by about 10% or more as compared to before administration.

[0244] 9. A composition comprising an oligonucleotide that targets ANGPTL4 and increases insulin sensitivity when administered to a subject in an effective amount.

[0245] 10. The composition of embodiment 9, wherein insulin sensitivity is increased by about 10% or more as compared to before administration.

[0246] 11. The composition of any one of embodiments 1-10, wherein the oligonucleotide comprises a modified internucleoside linkage.

[0247] 12. The composition of embodiment 11, wherein the modified internucleoside linkage comprises an alkylphosphonate, a phosphorothioate, a methylphosphonate, a phosphorodithioate, an alkylphosphonothioate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamidate, or a carboxymethyl ester, or a combination thereof.

[0248] 13. The composition of embodiment 11, wherein the modified internucleoside linkage comprises one or more phosphorothioate linkages.

[0249] 14. The composition of any one of embodiments 1-13, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.

[0250] 15. The composition of any one of embodiments 1-14, wherein the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, In some embodiments, the present invention comprises at least one modified internucleoside linkage, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0251] 16. The composition of any one of embodiments 1-15, wherein the oligonucleotide comprises modified nucleosides.

[0252] 17. The composition of embodiment 16, wherein the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro or a 2'-deoxy, or a combination thereof.

[0253] 18. The composition of embodiment 16, wherein the modified nucleoside comprises LNA.

[0254] 19. The composition of embodiment 16, wherein the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid.

[0255] 20. The composition of embodiment 16, wherein the modified nucleosides comprise 2'-O-methyl nucleosides, 2'-deoxyfluoro nucleosides, 2'-ON-methylacetamido (2'-O-NMA) nucleosides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleosides, 2'-O-aminopropyl (2'-O-AP) nucleosides, or 2'-ara-F, or a combination thereof.

[0256] 21. The composition of embodiment 16, wherein the modified nucleosides include one or more 2' fluoro-modified nucleosides.

[0257] 22. The composition of embodiment 16, wherein the modified nucleoside comprises a 2'O-alkyl modified nucleoside.

[0258] 23. The composition of embodiment 16, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide.

[0259] 24. The composition of embodiment 23, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof.

[0260] 25. The composition of any one of embodiments 1-24, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

[0261] 26. The composition of any one of the embodiments 1-25, wherein the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0262] 27. The composition of any one of embodiments 1-26, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.

[0263] 28. The composition of any one of embodiments 1-27, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0264] 29. The composition of embodiment 28, wherein the sense strand is 14-30 nucleosides in length.

[0265] 30. The composition of embodiment 28 or 29, wherein the antisense strand is 14-30 nucleosides in length.

[0266] 31. A composition comprising an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of SEQ ID NO: 13935.

[0267] 32. A composition comprising an oligonucleotide that inhibits expression of ANGPTL4, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of SEQ ID NO: 13936.

[0268] 33. The composition of any one of embodiments 28-32, wherein the sense strand and the antisense strand form a double-stranded RNA duplex.

[0269] 34. The composition of embodiment 33, wherein the first base pair of the double-stranded RNA duplex is an AU base pair.

[0270] 35. The composition of any one of embodiments 28-34, wherein the sense strand comprises a 3' overhang comprising 1, 2, or more nucleosides.

[0271] 36. The composition of embodiment 35, wherein the 3' overhang of the sense strand comprises 2 nucleosides.

[0272] 37. The composition of any one of embodiments 28-36, wherein the antisense strand comprises a 3' overhang comprising 1, 2, or more nucleosides.

[0273] 38. The composition of embodiment 37, wherein the 3' overhang of the antisense strand comprises 2 nucleosides.

[0274] 39. The composition of any one of embodiments 28-38, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

[0275] 40. The composition of any one of embodiments 28-39, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977.

[0276] 41. The composition of any one of embodiments 28-40, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

[0277] 42. The composition of any one of embodiments 28-41, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985.

[0278] 43. The composition of any one of embodiments 28-42, wherein the siRNA binds to a 17-mer in non-human primate ANGPTL4 mRNA.

[0279] 44. The composition of any one of embodiments 28-43, wherein the siRNA binds to the 19-mer in human ANGPTL4 mRNA.

[0280] 45. The composition of any one of embodiments 28-44, wherein the siRNA binds to human ANGPTL4 mRNA and fewer than or equal to 20 human off-targets with no more than 2 mismatches in the antisense strand.

[0281] 46. ​​The composition of any one of embodiments 28-45, wherein the siRNA binds to a human ANGPTL4 mRNA target site that does not have a SNP (positions 2-18) with a minor allele frequency (MAF) greater than or equal to 1%.

[0282] 47. The composition of any one of embodiments 28-46, wherein the sense strand comprises SEQ ID NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 1 16, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 1 54, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177, 1 96, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 2 28, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 388, 391, 392, 393, 3 94, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 680 79, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009,1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1164, 1165 65, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430 、1448、1477、1487、1488、1489、1493、1494、1519、1523、1538、1556、1561、1563、1564、1565、1570、1571、1572、1580、1581、1589、1597、1598、1601、1602、1603、1604、1605、1606、1610、1611、1613、1614、1617、1693、1 699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802 or 1803, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions; and wherein the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933 , 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1 983, 2003, 2004, 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070,2071、2072、2073、2075、2076、2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911、2912、2918、2966、2976、2978, 2980, 2981, 2987, 2988, 2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106 , 3107, 3113, 3130, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347 , 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 3547, 3553, 3555 , 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656 or 3657, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.

[0283] 48. The composition of any one of embodiments 28-47, wherein the sense strand comprises SEQ ID NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 84, 111, 112, 1 16, 117, 118, 119, 120, 121, 125, 126, 127, 128, 129, 149, 150, 152, 153, 1 54, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 177, 1 96, 198, 199, 210, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 2 28, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 282, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 377, 380, 382, ​​386, 388, 391, 392, 393, 3 94, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 417, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 481, 484, 506, 509, 517, 519, 520, 565, 570, 571, 572, 589, 607, 608, 610, 611, 612, 616, 617, 620, 623, 635, 637, 640, 643, 653, 672, 673, 674, 675, 676, 677, 678, 680 79, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 834, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 859, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 897, 900, 902, 907, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 925, 945, 968, 1001, 1002, 1005, 1006, 1009,1010, 1011, 1013, 1028, 1032, 1037, 1052, 1053, 1054, 1055, 1057, 1058, 1064, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1136, 1137, 1147, 1148, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1163, 1 164, 1165, 1166, 1171, 1172, 1175, 1181, 1182, 1184, 1248, 1249, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1338, 1343, 1347, 1348, 1349, 1350, 1351, 1352, 1378, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418 8. 1429, 1430, 1448, 1477, 1487, 1488, 1489, 1493, 1494, 1519, 1523, 1538, 1556, 1561, 1563, 1564, 1565, 1570, 1571, 1572, 1580, 1581, 1589, 1597, 1598, 1601, 1602, 1603, 1604, 1605, 1606, 1610, 1611, 1613 , 1614, 1617, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1787, 1788, 1798, 1799, 1800, 1801, 1802 or 1803; and wherein the antisense strand comprises SEQ ID NO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 1918, 1933, 1934, 1938, 1965, 1966, 1970, 1971, 1972, 1973, 1974, 1975, 1979, 1980, 1981, 1982, 1983, 2003, 200 4. 2006, 2007, 2008, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2031, 2050, 2052, 2053, 2064, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2075, 2076,2077、2082、2084、2085、2094、2095、2099、2100、2104、2106、2107、2108、2109、2114、2115、2116、2117、2119、2120、2125、2126、2128、2134、2136、2143、2144、2145、2146、2147、2153、2158、2175、2177、2179、2180、2182、2183、2184、2185、2186、2187、2188、2189、2191、2192、2193、2196、2201、2203、2204、2206、2207、2210、2231、2234、2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2271、2273、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2335、2338、2360、2363、2371、2373、2374、2419、2424、2425、2426、2443、2461、2462、2464、2465、2466、2470、2471、2474、2477、2489、2491、2494、2497、2507、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2688、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2713、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2751、2754、2756、2761、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2779、2799、2822、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2891、2906、2907、2908、2909、2911、2912、2918、2966、2976、2978、2980、2981、2987、2988、2990, 2991, 3001, 3002, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015, 3016, 3017, 3018, 3019, 3020, 3025, 3026, 3029, 3035, 3036, 3038, 3102, 3103, 3106, 3107, 3113, 3114 30, 3139, 3164, 3169, 3192, 3197, 3201, 3202, 3203, 3204, 3205, 3206, 3232, 3259, 3261, 3267, 3268, 3269, 3270, 3271, 3272, 3283, 3284, 3302, 3331, 3341, 3342, 3343, 3347, 3348, 3373, 3377, 3392, 3410, 3415, 3417, 3418, 3419, 3424, 3425, 3426, 3434, 3435, 3443, 3451, 3452, 3455, 3456, 3457, 3458, 3459, 3460, 3464, 3465, 3467, 3468, 3471, 35 47, 3553, 3555, 3556, 3557, 3576, 3594, 3595, 3596, 3599, 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3641, 3642, 3652, 3653, 3654, 3655, 3656, or 3657.

[0284] 49. The composition of any one of embodiments 28-48, wherein the sense strand comprises SEQ ID NO:33, 34, 35, 36, 56, 121, 272, 280, 282, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342 ,347,349,411,412,430,431,435,481,484,509,517,519,520,565,620,635,637,640,830,834,841,842,843,844,850,871,872,876,8 the nucleotide sequence of any one of 87, 888, 894, 897, 902, 945, 1001, 1002, 1005, 1037, 1133, 1134, 1137, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1171, 1172, 1248, 1249, 1315, 1338, 1343, 1347, 1348, 1429, 1430, 1570, 1571, 1572, 1610, 1611, 1617, 1780, 1784, or 1787;and wherein the antisense strand comprises SEQ ID NO: 1887, 1888, 1889, 1890, 1910, 1975, 2126, 2134, 2136, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 21 91, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2335, 2338, 2363, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2684, 2688, 2695, 2696, 2697 7, 2698, 2704, 2725, 2726, 2730, 2741, 2742, 2748, 2751, 2756, 2799, 2855, 2856, 2859, 2891, 2987, 2988, 2991, 3003, 3005, 3007, 3008, 3009, 3011, 3012, 3015 , 3016, 3018, 3019, 3020, 3025, 3026, 3102, 3103, 3169, 3192, 3197, 3201, 3202, 3283, 3284, 3424, 3425, 3426, 3464, 3465, 3471, 3634, 3638, or 3641. ;

[0285] 50. The composition of any one of embodiments 28-49, wherein the sense strand comprises SEQ ID NO:32, 33, 34, 35, 36, 56, 57, 58, 59, 61, 62, 63, 64, 79, 80, 112, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129, 149, 150, 152, 153, 157, 158, 159, 161, 164, 165, 166, 167, 168, 169, 172, 174, 175, 196, 199, 211, 212, 214, 215, 216, 217, 218, 219, 221, 222, 223, 228, 230, 231, 240, 241, 245, 246, 250, 252, 253, 254, 255, 260, 261, 262, 263, 265, 266, 271, 272, 274, 280, 289, 290, 291, 292, 293, 299, 304, 321, 323, 325, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 350, 352, 353, 356, 380, 382, ​​386, 388, 391, 392, 393, 394, 397, 398, 399, 402, 404, 405, 411, 412, 413, 414, 415, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 435, 484, 517, 519, 520, 565, 570, 571, 572, 607, 608, 610, 611, 612, 616, 617, 620, 635, 637, 640, 672, 673, 674, 675, 676, 677, 678, 679, 681, 682, 683, 684, 686, 687, 689, 692, 695, 830, 841, 842, 843, 844, 850, 851, 852, 853, 854, 856, 857, 866, 868, 871, 872, 876, 887, 888, 890, 892, 893, 894, 902, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 945, 1001, 1002, 1005, 1006, 1009, 1010, 1011, 1013, 1028, 1032, 1052, 1053, 1054, 1055, 1057, 1058, 1112, 1122, 1124, 1126, 1127, 1133, 1134, 1147, 1148,1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1175, 1182, 1184, 1252, 1253, 1259, 1276, 1285, 1310, 1315, 1343, 1347, 1348, 1349, 1350, 1351, 1405, 1407, 1413, 1414, 1415, 1416, 1417, 1418, 1429, 1430, 1448, 1519, 1523, 1556, 1561, 1563, 1564, 1570 65, 1571, 1572, 1580, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1611, 1613, 1614, 1693, 1699, 1701, 1702, 1703, 1722, 1740, 1741, 1742, 1745, 1747, 1748, 1749, 1751, 1754, 1755, 1779, 1780, 1784, 1788, 1798, 1799, 1801, 1802 or 1803; and wherein the antisense strand comprises SEQ IDNO:1886, 1887, 1888, 1889, 1890, 1910, 1911, 1912, 1913, 1915, 1916, 1917, 191 8. 1933, 1934, 1966, 1970, 1971, 1972, 1973, 1974, 1979, 1980, 1981, 1982, 1983, 2 2003, 2004, 2006, 2007, 2011, 2012, 2013, 2015, 2018, 2019, 2020, 2021, 2022, 2023, 2026, 2028, 2029, 2050, 2053, 2065, 2066, 2068, 2069, 2070, 2071, 2072, 2073, 2074 75, 2076, 2077, 2082, 2084, 2085, 2094, 2095, 2099, 2100, 2104, 2106, 2107, 2108, 2109, 2114, 2115, 2116, 2117, 2119, 2120, 2125, 2126, 2128, 2134, 2143, 2144, 2145 5. 2146, 2147, 2153, 2158, 2175, 2177, 2179, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2204, 2206, 2207, 2210, 2234,2236、2240、2242、2245、2246、2247、2248、2251、2252、2253、2256、2258、2259、2265、2266、2267、2268、2269、2274、2275、2276、2277、2278、2279、2280、2281、2282、2283、2284、2285、2289、2338、2371、2373、2374、2419、2424、2425、2426、2461、2462、2464、2465、2466、2470、2471、2474、2489、2491、2494、2526、2527、2528、2529、2530、2531、2532、2533、2535、2536、2537、2538、2540、2541、2543、2546、2549、2684、2695、2696、2697、2698、2704、2705、2706、2707、2708、2710、2711、2720、2722、2725、2726、2730、2741、2742、2744、2746、2747、2748、2756、2765、2766、2767、2768、2769、2770、2771、2772、2773、2774、2775、2776、2799、2855、2856、2859、2860、2863、2864、2865、2867、2882、2886、2906、2907、2908、2909、2911、2912、2966、2976、2978、2980、2981、2987、2988、3001、3002、3003、3005、3007、3008、3009、3011、3012、3015、3016、3018、3019、3020、3029、3036、3038、3106、3107、3113、3130、3139、3164、3169、3197、3201、3202、3203、3204、3205、3259、3261、3267、3268、3269、3270、3271、3272、3283、3284、3302、3373、3377、3410、3415、3417、3418、3419、3425、3426、3434、3435、3443、3451、3455、3456、3457、3458、3459、3460、3465、3467、3468、3547、3553、3555、3556、3557、3576、3594、3595、3596、3599、The nucleotide sequence of any one of 3601, 3602, 3603, 3605, 3608, 3609, 3633, 3634, 3638, 3642, 3652, 3653, 3655, 3656 or 3657.

[0286] 51. The composition of any one of embodiments 28-50, wherein the sense strand comprises SEQ ID NO: 33, 34, 35, 36, 56, 272, 280, 289, 290, 291, 292, 293, 321, 323, 326, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 342, 347, 349, 411, 412, 430, 431, 435, 484, 517, 519, 520, 565, 620, 635, 637, 640, 830, 841, 842, 843, 844, 850, 851, 852, 853, 854, 855 71, 872, 876, 887, 888, 894, 902, 945, 1001, 1002, 1005, 1133, 1134, 1149, 1151, 1153, 1154, 1155, 1157, 1158, 1161, 1162, 1164, 1165, 1166, 1315, 1343, 1347, 1348, 1429, 1430, 1571, 1572, 1611, 1780, or 1784; and wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NO:1887, 1888, 1889, 1890, 1910, 2126, 2134, 2143, 2144, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2183, 2184, 2185, 2186, 2187, 2 188, 2189, 2191, 2192, 2193, 2196, 2201, 2203, 2265, 2266, 2284, 2285, 2289, 2338, 2371, 2373, 2374, 2419, 2474, 2489, 2491, 2494, 2 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

[0287] 52. The composition of any one of embodiments 28-51, wherein the antisense strand comprises a seed region that is different from a seed region of a human miRNA.

[0288] 53. The composition of any one of embodiments 28-52, wherein the sense strand comprises SEQ ID NO: 32, 36, 56, 57, 58, 61, 62, 79, 80, 117, 119, 125, 126, 128, 149, 152, 157, 158, 159, 161, 165, 166, 167, 168, 169, 174, 196, 211, 212, 217, 218, 219, 230, 231, 245, 246, 253, 260, 261, 262, 271, 272, 280, 289, 291, 292, 293, 304, 321, 323, 325, 326 6, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 352, 353, 356, 380, 382, ​​386, 388, 391, 392, 394, 399, 413, 414, 415, 422, 423, 424, 425, 426, 435, 517, 519, 520, 565, 571, 607, 608, 612, 617, 620, 635, 640, 672, 673, 674, 675, 678, 679, 68 1, 683, 684, 687, 692, 842, 843, 850, 851, 854, 866, 868, 876, 892, 893, 902, 911, 912, 913, 914, 916, 919, 945, 1001, 1002, 1006, 1010, 1028, 1052, 1053, 1054, 1055, 1057, 1112, 1124, 1127, 1147, 1149, 1151, 1153, 1155, 1157, 1164, 1175, 1182, the nucleotide sequence of any one of 1184, 1259, 1276, 1285, 1315, 1343, 1349, 1350, 1351, 1405, 1407, 1413, 1415, 1418, 1564, 1571, 1581, 1589, 1597, 1601, 1602, 1603, 1604, 1605, 1606, 1613, 1614, 1693, 1701, 1722, 1740, 1745, 1751, 1755, 1801, 1802, or 1803, or 3638;and wherein the antisense strand comprises SEQ ID NO: 1886, 1890, 1910, 1911, 1912, 1915, 1916, 1933, 1934, 1971, 1973, 1979, 1980, 1982, 2003, 2006, 2011, 2012, 2013, 2015, 2019, 2020, 2021, 2022, 2023, 2028, 2050, 2065, 2066, 2071, 2072, 2073, 2084, 2085, 2099, 2100, 2107, 2114, 2115, 2116, 2125, 2126, 2134, 2143, 2145, 2146 、2147、2158、2175、2177、2179、2180、2182、2184、2185、2186、2187、2188、2191、2192、2196、2201、2203、2206、2207、2210、2234、2236、2240、2242、2245、2246、2248、2253、2267、2268、2269、2276、2277、2278、2279、2280、2289、2371、2373、2374、2419、2425、2461、2462、2466、2471、2 474, 2489, 2494, 2526, 2527, 2528, 2529, 2532, 2533, 2535, 2537, 2538, 2541, 2546, 2696, 2697, 2704, 2705, 2708, 2720, 2722, 2730, 2746, 2747, 2756, 2765, 2766, 2767, 2768, 2770, 2773, 2799, 2855, 2856, 2860, 2864, 2882, 2906, 2907, 2908, 2909, 2911, 2966, 2978, 2981, 3001, 300 3. the nucleotide sequence of any one of 3005, 3007, 3009, 3011, 3018, 3029, 3036, 3038, 3113, 3130, 3139, 3169, 3197, 3203, 3204, 3205, 3259, 3261, 3267, 3269, 3272, 3418, 3425, 3435, 3443, 3451, 3455, 3456, 3457, 3458, 3459, 3460, 3467, 3468, 3547, 3555, 3576, 3594, 3599, 3605, 3609, 3655, 3656, or 3657.

[0289] 54. The composition of any one of embodiments 28-53, wherein the sense strand comprises the nucleotide sequence of any one of SEQ ID 36, 56, 272, 280, 289, 291, 292, 293, 321, 323, 326, 328, 330, 331, 332, 333, 334, 337, 338, 342, 347, 349, 435, 517, 519, 520, 565, 620, 635, 640, 842, 843, 850, 876, 902, 945, 1001, 1002, 1149, 1151, 1153, 1155, 1157, 1164, 1315, 1343, or 1571; and wherein the antisense strand comprises the nucleotide sequence of any one of SEQ ID 1890, 1910, 2126, 2134, 2143, 2145, 2146, 2147, 2175, 2177, 2180, 2182, 2184, 2185, 2186, 2187, 2188, 2191, 2192, 2196, 2201, 2203, 2289, 2371, 2373, 2374, 2419, 2474, 2489, 2494, 2696, 2697, 2704, 2730, 2756, 2799, 2855, 2856, 3003, 3005, 3007, 3009, 3011, 3018, 3169, 3197, or 3425.

[0290] 55. The composition of any one of embodiments 28-54, wherein the sense strand comprises a seed region that is different from a seed region of a human miRNA.

[0291] 56. The composition of any one of embodiments 28-55, wherein the sense strand comprises SEQ ID NO:32, 36, 56, 58, 61, 62, 80, 117, 119, 126, 152, 154, 157, 158, 159, 161, 1 66, 169, 174, 177, 196, 211, 212, 217, 218, 230, 231, 245, 253, 260, 261, 27 1. 272, 280, 289, 293, 304, 328, 330, 331, 332, 333, 334, 3...

Claims

1. A composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and reduces expression of ANGPTL4 when administered to a subject in an effective amount, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide sequence of SEQ ID NO: 13973, wherein at least one internucleoside linkage is modified and at least one nucleoside is a modified nucleoside; and wherein the antisense strand comprises the oligonucleotide sequence of SEQ ID NO: 13981, wherein at least one internucleoside linkage is modified and at least one nucleoside is a modified nucleoside; wherein the modified nucleosides include 2'-fluoro nucleosides or 2'-O-methyl nucleosides or a combination thereof; wherein the oligonucleotide comprises a GalNAc ligand attached to the 3' or 5' end of the sense strand.

2. compositions as claimed in claim 1, wherein said modified internucleoside linking bond comprises alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetamide ester or carboxymethyl ester or its combination.

3. The composition of claim 1, wherein the modified internucleoside linkage comprises a phosphorothioate linkage.

4. The composition of claim 1, wherein the sense strand comprises 2-6 modified internucleoside linkages.

5. The composition of claim 1, wherein the antisense strand comprises 2-6 modified internucleoside linkages.

6. The composition of claim 1, wherein the modified nucleoside comprises a 2'-fluoro modified nucleoside.

7. The composition of claim 1, wherein the modified nucleosides comprise 2'-O-methyl modified nucleosides.

8. The composition of claim 1, wherein the sense strand or antisense strand comprises 15-21 modified nucleosides.

9. The composition of claim 1, wherein the sense strand or the antisense strand comprises a 3' overhang of at least 2 nucleosides.

10. The composition of claim 9, wherein the 3' overhang comprises one or more uridine nucleosides.

11. The composition of claim 10, wherein the one or more uridine nucleosides of the overhang are linked to another nucleoside at the 3' end via phosphorothioate.

12. The composition of claim 1, wherein the oligonucleotide comprises 3 GalNAc moieties.

13. The composition of claim 1, wherein the GalNAc ligand is attached to the 5' end of the sense strand.

14. The composition of claim 1, wherein the GalNAc ligand is attached to the 3' end of the sense strand.

15. The composition of claim 1, wherein the sense strand comprises modification pattern 1S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13954), modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 13955), modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 13956), or modification pattern 6S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 13957). 13959); wherein "Nf" is a 2'-fluoro modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, "s" is a phosphorothioate linkage, and N includes the nucleoside.

16. The composition of claim 1, wherein the antisense strand comprises modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 13960), modification pattern 2AS: 5'-nsNfsnnnNfNfnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13961), modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13962), modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13963), modification pattern 5AS: 5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13964). 13964), modification pattern 6AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 13965), modification pattern 7AS: 5'-nsNfsnNfnNfnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 13966), modification pattern 8AS: 5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3' (SEQ ID NO: 13967) or modification pattern 9AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3' (SEQ ID NO: 13968); wherein "Nf" is a 2'-fluoro modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

17. The composition of claim 1, wherein the antisense strand comprises the oligonucleotide sequence of SEQ ID NO: 13985.

18. The composition of claim 17, wherein the sense strand comprises the oligonucleotide sequence in SEQ ID NO: 13977.

19. The composition of claim 1, wherein the antisense strand comprises the modification pattern 6AS.

20. The composition of claim 1, wherein the sense strand comprises a modification pattern of 2S, and the antisense strand comprises a modification pattern of 3AS or 6AS.

Images