Oligonucleotides for treating angiopoietin-like 4 (ANGPTL4) related diseases

Abstract

In one embodiment, a composition is provided comprising an oligonucleotide that targets angiogenin-like 4 (ANGPTL4). The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a metabolic or cardiovascular disorder by providing an oligonucleotide targeting ANGPTL4 to a subject in need thereof.

Description

[0001] This application is a divisional application of the Chinese patent application with application date of December 8, 2020, application number 202080096133.7, and invention name “Oligonucleotides for treating angiopoietin-like 4 (ANGPTL4) related diseases” (the application date of the corresponding PCT application is December 8, 2020, and application number PCT / US2020 / 063824).

[0002] Cross-references

[0003] 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.

[0004] Incorporation by Reference to the Sequence Listing

[0005] 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

[0006] Cardiovascular and metabolic disorders are becoming increasingly numerous and may affect a wide variety of people. Improved therapies to treat these disorders are needed. Summary of the invention

[0007] In some embodiments, compositions are disclosed herein, comprising oligonucleotides that target angiopoietin-like 4 (ANGPTL4) and that, 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 oligonucleotides include 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 a 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 a nucleotide sequence of SEQ ID NO: 13936 and having 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 sequences.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 a 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 has at least 85% identical 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 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 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 nucleosides include locked nucleic acids (LNA), hexitol nucleic acids (HLA), cyclohexene nucleic acids (CeNA), 2',4' constrained ethyl, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, 2'-deoxy, 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, 2'ara-F, or a combination thereof. In some embodiments, the modified nucleosides include 2'fluoro modified nucleosides. In some embodiments, the modified nucleosides include 2'O methyl modified nucleosides. In some embodiments, the sense strand or antisense strand comprises 15-21 modified nucleosides. In some embodiments, the sense strand or 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'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), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3' (SEQ ID NO: 13957), modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsnN-3' (SEQ ID NO: 13958). NO:13958), modification pattern 6S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn3' (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'nsNfsnnnNfNfNfnnnnNfnNfnnnsnsn-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'nsNfsnnnnnnnnnnnNfnnnnnsnsn3'(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.

[0008] Disclosed herein are methods of 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 targeting 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 a 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 reduces a triglyceride measurement, reduces a cholesterol measurement, reduces a glucose measurement, increases a HDL measurement, or increases an insulin sensitivity measurement 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 a nucleotide sequence of SEQ ID NO: 13935 and has no more than 2 mismatches. In some embodiments, the antisense strand comprises a nucleotide sequence of SEQ ID NO: 13936 and having 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 sequences.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, 2992, 2993, 2994, 2995, 2996, 2997, 2998, 2999, 2999, 2991, 2993, 2999, 2994, 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 a 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 has at least 85% identical 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, 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 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 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'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), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3' (SEQ ID NO: 13957), modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsnN-3' (SEQ ID NO: 13958). NO:13958), modification pattern 6S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn 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'nsNfsnnnNfNfNfnnnnNfnNfnnnsnsn-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'nsNfsnnnnnnnnnnnNfnnnnnsnsn3'(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.

[0009] Disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 4 (ANGPTL4) and that reduce circulating triglycerides when administered to a subject in an effective amount. 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 reduce circulating total cholesterol when administered to a subject in an effective amount. 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 increase circulating high-density lipoprotein (HDL) when administered to a subject in an effective amount. 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 reduce circulating glucose when administered to a subject in an effective amount. 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 as compared to before administration. In some embodiments, the oligonucleotides include 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 oligonucleotides include siRNAs comprising a sense strand and an antisense strand, each strand being independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence of about 14-30 consecutive nucleosides containing SEQ ID NO: 13935. Also disclosed herein are compositions comprising oligonucleotides that inhibit the expression of ANGPTL4, wherein the oligonucleotide comprises a 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 of about 14-30 consecutive nucleosides comprising 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 NO: 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 containing 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 containing 1, 2 or more nucleosides. In some embodiments, the siRNA binds to a 19mer in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 17mer in non-human primate ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 19mer in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a 19mer in human ANGPTL4 mRNA. In some embodiments, the siRNA binds to a human ANGPTL4 mRNA and less than or equal to 20 human off-targets with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds 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: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, 2 107, 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 having 1 or 2 nucleoside substitutions, additions, or deletions thereof. 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, 15 1780, 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 ,640,830,834,841,842,843,844,850,871,872,876,887,888,894,897,902, 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, 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: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 having 1 or 2 nucleoside substitutions, additions, or deletions thereof. 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 having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand comprises SEQ ID 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 having 1 or 2 nucleoside substitutions, additions, or deletions therein. 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, 400 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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 a 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 having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand comprises a seed region that is different from a 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 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, 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 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, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand and / or the antisense strand further comprises a nucleotide sequence comprising 1,2 or more nucleosides 3' overhang. 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, an aminophosphorate, a carbamate, a carbonate, a phosphotriester, an acetamide ester 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-methylacetylamino (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, modified nucleosides include one or more 2'fluorine-modified nucleosides. In some embodiments, 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, docosanoyl, docosahexenoyl, myristyl, palmitylstearyl or alpha-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, 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 comprise 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 a 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; and a modification pattern 1S. 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 nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions; and a modification pattern 2S. 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 nucleoside substitutions, additions or deletions; and a modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleoside sequence and modification pattern 1AS, the 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 comprises a nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NOs: 1855-3708 or 13978-13985; or a sequence having 1 or 2 nucleoside substitutions,Added or deleted nucleic acid sequence; and modification pattern 3AS. In some embodiments, the antisense strand comprises a nucleoside sequence and a modification pattern 3AS, the nucleoside sequence comprising or consisting of the following: a sequence of any one of SEQ ID NO: 1855-3708 or 13978-13985. In some embodiments, the oligonucleotide comprises an ASO. In some embodiments, the ASO is 12-30 nucleosides in length. Also disclosed herein is a composition comprising an oligonucleotide that inhibits 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 a modification comprising a modified nucleoside and / or a modified internucleoside linkage, 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 a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO 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. 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'-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 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 and a modification pattern ASO1, wherein the nucleotide sequence comprises or consists of the sequence of any one of SEQ ID NO: 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.

[0010] DETAILED DESCRIPTION

[0011] 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 relatively evenly distributed genetic variants on the genome. The most common GWAS design is a case-control study, which involves comparing the variant frequencies 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 (OR) as a measure of effect size; or beta coefficients (β) as a measure of effect size. Researchers usually assume an additive genetic model and calculate the allele advantage ratio, which is the increased (or reduced) 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 a non-random association of alleles. The presence of linkage disequilibrium may obfuscate which variant is "causal".

[0012] Functional annotation of variants and / or wet laboratory experiments can identify 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 insight into the potential therapeutic efficacy and safety of therapeutic agents that regulate the target.

[0013] 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, 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 treatments, such as small molecules and monoclonal antibodies; mature methods, such as oligonucleotides; and emerging methods, such as gene therapy and gene editing. The choice of treatment may depend on several factors, including the location of the target (e.g., intracellular, extracellular, or secreted), relevant tissues (e.g., liver), and related indications.

[0014] 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 may 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 have a characteristic structure that includes an N-terminal coiled-coil domain that mediates homo-oligomerization and a C-terminal fibrinogen domain that is involved in signaling.

[0015] 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 is most highly expressed in the liver and adipose tissue in humans. 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.

[0016] Circulating triglycerides are strong and independent 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. In addition, mutations in TRL genes may cause inherited disorders, including familial chylomicronemia syndrome and familial hypertriglyceridemia. Here, genetic variants that cause inactivation of ANGPTL4 in humans have been shown to be associated with reduced triglycerides, increased HDL, and reduced risk of diabetes and cardiovascular disease. Therefore, inhibition of ANGPTL4 may serve as a therapeutic strategy for treating a range of cardiometabolic diseases.

[0017] Disclosed herein are compositions 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.

[0018] I. Composition

[0019] In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise oligonucleotides targeting angiopoietin-like 4 (ANGPTL4). In some embodiments, the compositions consist of oligonucleotides targeting ANGPTL4. In some embodiments, the compositions described herein are used in methods of treating a disorder in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in methods of treating a disorder as described herein. Some embodiments relate to the use of compositions comprising oligonucleotides in methods of treating a disorder as described herein.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces ANGPTL4 mRNA levels in a cell or tissue when administered to a subject in an effective amount. 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% as 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% as 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.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces circulating ANGPTL4 protein levels in cells or tissues when administered to a subject in an effective amount. In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces ANGPTL4 protein levels in a fluid (such as blood, serum, or plasma) when administered to a subject in an effective amount. In some embodiments, the ANGPTL4 protein level 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, the ANGPTL4 protein level is reduced by about 10% or more, as compared to before administration. In some embodiments, the ANGPTL4 protein level 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, the ANGPTL4 protein level 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, the ANGPTL4 protein level is reduced by no more than about 10% as compared to before administration. In some embodiments, the ANGPTL4 protein level 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, the ANGPTL4 protein level 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.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces circulating triglycerides when administered to a subject in an effective amount. 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% as 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.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces circulating cholesterol when administered to a subject in an effective amount. 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 the range defined by any two of the aforementioned percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and increases circulating high-density lipoprotein (HDL) when administered to a subject in an effective amount. In some embodiments, circulating HDL 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, circulating HDL is increased by about 10% or more, as compared to before administration. In some embodiments, circulating HDL 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, circulating HDL 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, HDL 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, HDL is reduced by no more than about 10% as 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% as 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% as 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.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces circulating glucose when administered to a subject in an effective amount. 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.

[0026] 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.

[0027] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL4 and reduces circulating insulin when administered to a subject in an effective amount. 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.

[0028] A.siRNA

[0029] 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.

[0030] 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.

[0031] 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 a 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 a nucleotide sequence of SEQ ID NO: 13935, and each strand has 12 to 30 nucleotides.

[0032] 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.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a 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.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a 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 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.

[0035] 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 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.

[0036] 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 nucleoside sequence comprising or consisting of: a 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. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the 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 nucleotide range 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 following: a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, or a nucleic acid sequence having 1 or 2 nucleosides added at 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.

[0037] 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.

[0038] 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 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 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence 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 3 or 4 nucleoside substitutions, additions, or deletions. 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 nucleotide range 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 following: a sequence of any one of SEQ ID NO: 1855-3708 or 13978-13985, or a nucleic acid sequence having 1 or 2 nucleosides added at the 3' end. A sequence of any one of SEQ ID NO: 1855-3708 or 13978-13985 may include a sequence of any one of SEQ ID NO: 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.

[0039] 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.

[0040] 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 siRNA binds to a 19-mer 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.

[0041] 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 siRNA binds to a 17-mer in a 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 in a non-human primate ANGPTL4 mRNA.

[0042] 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 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 and 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer in human ANGPTL4 mRNA.

[0043] 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 less than or equal to 20 human off-targets, wherein there are no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL4 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0044] 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%.

[0045] 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 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.

[0046] 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 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、 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.

[0047] 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 ,1938,1965,1966,1970,1971,1972,1973,1974,1975,1979,1980,1981,1982,1983,2003,2 004, 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, 3556 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 nucleosides added at the 3' end. For example, the nucleic acid sequence may have 2 uridine nucleosides added at the 3' end. The nucleic acid sequence may have 1 uridine nucleoside added at the 3' end. The nucleic acid sequence may have more than 2 nucleosides added at the 3' end.

[0048] 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 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 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, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2208, 2209, 2211 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, 269 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. ;

[0049] 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 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 of any one of the nucleotide sequence; 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.

[0050] 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 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 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 3014, 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

[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, 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, 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. ;

[0052] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, the sense strand comprising SEQ ID36, 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 a 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.

[0053] 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 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 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. ;

[0054] 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.

[0055] In some embodiments, the siRNA comprises the sense strand 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 strand 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 strand 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.

[0056] In some embodiments, the siRNA comprises the sense strand 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 strand 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 strand 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.

[0057] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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.

[0058] In some embodiments, the siRNA comprises the sense strand 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 strand 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 strand 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.

[0059] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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.

[0060] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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.

[0061] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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 strand and / or antisense strand sequence of the siRNA 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.

[0062] In some embodiments, the siRNA comprises the sense strand 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 strand 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 strand 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.

[0063] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 5, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 5, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand 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.

[0064] 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 siRNA. In some embodiments, the reduction is in response to 10 nM of siRNA.

[0065] Some of the siRNAs in Table 5 reduced ANGPTL mRNA measurements by 10% or more relative to controls. 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, ETD0069 ...9, ETD00691, ETD00693, ETD00694, ETD00695, ETD00696, ETD00697, ETD00698, ETD00699, ETD00691, ETD00692 736, ETD00738 or ETD00743, 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, ETD0069 ...9, ETD0069 736, ETD00738 or ETD00743, 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, 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, ETD00692, 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.

[0066] 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 the 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 the NHP ANGPTL4 mRNA.

[0067] 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[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 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 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, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the siRNA comprises 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. 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.

[0069] 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 an 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 an 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 may 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 may comprise modification pattern 1AS, 3AS, 4AS, 5AS, 7AS or 8AS.

[0070] 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.

[0071] 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: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, the sense strand sequence of any one of 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 of one or more of the internucleoside linkages and / or nucleoside modifications.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 14129, 14130, 14131, 14132, or 14133. In some embodiments, the siRNA is unmodified.

[0072] 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, 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 having 3 or 4 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, 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, 1423 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, 1423 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 14284, 14285, 14286, 14287, or 14288. In some embodiments, the siRNA is unmodified.

[0073] The siRNA may comprise an unmodified form of the sense strand sequence of the 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, 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, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 121 157, 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 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 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).

[0074] The siRNA may comprise an unmodified form of the antisense strand sequence of the 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 SEQ ID 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, the antisense strand sequence of any one of 3694 or 3696. The siRNA may comprise 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, the antisense strand sequence of any one of 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, 3 011, 3019, 3020, 3025, 3026, 3102, 3103, 3139, 3192, 3202, 3284, 3343, 3344, 3418, 3434, 3435, 3443, 3451, 3465, 3556, 3694 or 3696, and the modification patterns described herein (e.g., modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS).

[0075] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 7, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 7, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence 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.

[0076] 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[0077] In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 10, or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence of the siRNA in Table 10, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises the sense strand and / or antisense strand sequence 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.

[0078] 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[0079] 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[0080] 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).

[0081] 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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).

[0082] 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.

[0083] 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 thereof. 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.

[0084] 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 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 strand and / or antisense strand comprises 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, or a sense strand 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 a 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. 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.

[0085] 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. A 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. A 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.

[0086] 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. A 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. A 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 a modification pattern 1S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a modification pattern 2S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a modification pattern 3S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a modification pattern 4S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a modification pattern 5S. The sense strand comprising the nucleoside sequence of SEQ ID NO: 13977 or its derivatives may comprise a modification pattern 6S.

[0087] 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 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 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 a nucleotide sequence of SEQ ID NO: 13981. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise an overhang of 2 nucleotides. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a modification pattern 1AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a modification pattern 2AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a modification pattern 3AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a modification pattern 4AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof may comprise a modification pattern 5AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13981 or a derivative thereof 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.

[0088] 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 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 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 a nucleotide sequence of SEQ ID NO: 13985. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a GalNAc ligand (e.g., attached to the 3' or 5' end). The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise an overhang of 2 nucleotides. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a modification pattern 1AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a modification pattern 2AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a modification pattern 3AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a modification pattern 4AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof may comprise a modification pattern 5AS. The antisense strand comprising a nucleoside sequence of SEQ ID NO: 13985 or a derivative thereof 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.

[0089] 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 a nucleoside sequence of any one of SEQ ID NOs: 14158-14166. The antisense strand may comprise a GalNAc ligand.

[0090] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13970 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13970 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13978 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[0091] In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13971 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand comprising a sequence of SEQ ID NO: 13971 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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 having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand comprising a sequence of SEQ ID NO: 13979 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. 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.

[0092] In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13972 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13972 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13980 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13980 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13980. 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 containing a sequence of SEQ ID NO: 13973 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13973 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13981 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13981 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13981. 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 containing a sequence of SEQ ID NO: 1285 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 1285 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 3139 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 3139 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 3139. 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 containing a sequence of SEQ ID NO: 1580 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 1580 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 3434 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 3434 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 3434. 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 containing a sequence of SEQ ID NO: 13974 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13974 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13982 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13982 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13982. 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 containing a sequence of SEQ ID NO: 13975 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13975 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13983 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13983 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13983. 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 containing a sequence of SEQ ID NO: 13976 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13976 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13984 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13984 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13984. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0099] In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13977 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing a sequence of SEQ ID NO: 13977 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises a sense strand containing 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 containing a sequence of SEQ ID NO: 13985 or a nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13985 or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the siRNA comprises an antisense strand containing a sequence of SEQ ID NO: 13985. In some embodiments, the antisense strand comprises one or more internucleoside linkages and / or nucleoside modifications.

[0100] 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 the NHP ANGPTL4 mRNA.

[0101] B.ASO

[0102] 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.

[0103] In some embodiments, the composition comprises an oligonucleotide that inhibits 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 that is complementary to about 12-30 consecutive 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.

[0104] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an ASO having a length of about 12-30 nucleosides and comprising a nucleoside sequence that is complementary to about 12-30 consecutive 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.

[0105] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises an ASO comprising a nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 3709-13934. 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 nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions thereof.

[0106] C. Modification Mode

[0107] 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 thiophosphate, a methylphosphonate, a dithiophosphate, an alkylthiophosphonate, an aminophosphate, a carbamate, a carbonate, a phosphotriester, an acetamide ester or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more thiophosphate linkages. The benefits of the modified internucleoside linkage may include reduced toxicity or improved pharmacokinetics.

[0108] In some embodiments, the composition comprises an oligonucleotide that inhibits the 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 provides at least one modified internucleoside linkage, ...

[0109] 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 group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside includes 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 nucleoside includes 2'-O-methyl nucleosides. In some embodiments, the modified nucleoside includes 2'-deoxyfluoro nucleosides. In some embodiments, the modified nucleoside includes 2'-O-NMA nucleosides. In some embodiments, the modified nucleoside includes 2'-O-DMAEOE nucleosides. In some embodiments, the modified nucleoside includes 2'-O-aminopropyl (2'-O-AP) nucleosides. In some embodiments, the modified nucleoside includes 2'-ara-F. In some embodiments, the modified nucleoside includes one or more 2' fluorine modified nucleosides. In some embodiments, modified nucleosides include 2'O-alkyl modified nucleosides.Benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0110] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0111] 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, behenoyl, docosahexaenoyl, myristyl, palmitylstearoyl, or alpha-tocopherol, or a combination thereof.

[0112] 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. "GalNAc ligand" can refer to a ligand of an asialoglycoprotein receptor (e.g., on a hepatocyte), the ligand comprising one or more GalNAc moieties. The GalNAc ligand can bind to an asialoglycoprotein receptor (e.g., on a hepatocyte). The GalNAc ligand can comprise one or more GalNAc moieties. Examples of GalNAc moieties include GalNAc attached to a linker. The GalNAc ligand can comprise 3 GalNAc moieties. The GalNAc ligand can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more GalNAc moieties.

[0113] The GalNAc ligand can be conjugated to an oligonucleotide. The GalNAc ligand can be conjugated to the 5' end of an oligonucleotide. The GalNAc ligand can be conjugated to the 3' end of an oligonucleotide. The first GalNAc ligand can be conjugated to the 5' end of an oligonucleotide, and the second GalNAc ligand can be conjugated to the 3' end of an oligonucleotide. The GalNAc ligand can be conjugated to the 3' or 5' end of an ASO. The GalNAc ligand can be conjugated to the 3' or 5' end of the sense strand of an siRNA. The GalNAc ligand can be conjugated to the 3' end of the sense strand of an siRNA. The GalNAc ligand can be conjugated to the 5' end of the sense strand of an siRNA. The GalNAc ligand can be conjugated to the 3' or 5' end of the antisense strand of an siRNA. The GalNAc ligand can be conjugated to the 3' end of the antisense strand of an siRNA. The GalNAc ligand can be conjugated to the 5' end of the antisense strand of an 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.

[0114] 1. siRNA modification patterns

[0115] 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.

[0116] 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.

[0117] 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 preceding 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.

[0118] 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 modified nucleoside range 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.

[0119] In some embodiments, the sense strand or antisense strand further comprises at least 2 additional nucleosides attached to the 3' end of the sense strand or antisense strand. In some embodiments, the sense strand or antisense strand comprises 2 additional nucleosides attached to the 3' end of the sense strand or antisense strand. As part of the sense strand, the additional nucleosides may or may not be complementary to the ANGPTL4 mRNA. The additional nucleosides of the antisense strand may include uracil. The 2 additional nucleosides of the antisense strand may both include uracil.

[0120] In some embodiments, the sense strand or sense strand further comprises at least 2 additional nucleosides attached to the 3' end of the sense strand or antisense strand. In some embodiments, the sense strand or sense strand comprises 2 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 2 additional nucleosides of the sense strand can both include uracil.

[0121] 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 modification pattern 1S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-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 modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-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 modification pattern 4S: 5'-NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfnNfsnsnN-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 the 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.

[0122] 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 modification pattern 1 AS: 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 2 AS: 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'-nsNfsnnnNfnnnnnnnfnNfnnnsnsn-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'-nsNfsnNfnNfnnnnnnnfnNfnnnsnsn-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'-nsNfsnNfnNfnNfnNfnnnnNfnNfnnnsnsn-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'-nsNfsnnnNfnnnnnnnfnNfnNfnsnsn-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 may include a GalNAc ligand attached to the 3' end. Any of modification patterns 1AS-9AS may include a GalNAc ligand attached to the 5' end.

[0123] 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, the sense strand or the antisense strand comprises a modification pattern of AS01.

[0124] 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.

[0125] 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 nucleoside sequence comprising or consisting of a 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 nucleoside sequence comprising or consisting of a 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; and a modification pattern of 1S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern of 1S.

[0126] 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 nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 2S. 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 nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions; and a modification pattern 2S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern 2S.

[0127] 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 nucleoside sequence comprising or consisting of a 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 nucleoside sequence comprising or consisting of a 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; and a modification pattern of 3S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern of 3S.

[0128] 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 nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, and a modification pattern 4S. 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 nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions; and a modification pattern 4S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern 4S.

[0129] 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 nucleoside sequence comprising or consisting of a 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 nucleoside sequence comprising or consisting of a 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; and a modification pattern of 5S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern of 5S.

[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 sense strand comprises a nucleoside sequence comprising or consisting of a 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 nucleoside sequence comprising or consisting of a 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; and a modification pattern of 6S. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions, or deletions; and a modification pattern of 6S.

[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 a 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 a 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; and a modification pattern 1AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 1AS.

[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 a 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 a 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; and a modification pattern 2AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 2AS.

[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 a 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 a 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; and a modification pattern 3AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 3AS.

[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 a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 and a modification pattern 4AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 4AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 4AS.

[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 a 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 a 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; and a modification pattern 5AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 5AS.

[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 a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 and a modification pattern 6AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 6AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 6AS.

[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 a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 and a modification pattern 7AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 7AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 7AS.

[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 a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977 and a modification pattern 8AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 8AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 8AS.

[0139] 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: 1-1854 or 13970-13977 and a modification pattern 9AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 9AS. In some embodiments, the antisense strand comprises a nucleotide sequence comprising or consisting of a 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; and a modification pattern 9AS.

[0140] 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, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 1S. 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, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 2S. 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 comprises a nucleoside sequence comprising or consisting of a sequence of any one of SEQ ID NOs: 1-1854 or 13970-13977, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 3S. 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, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 4S. 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, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 5S. 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, an overhang (such as a 3' overhang of 2 bases), and a modification pattern 6S. 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 1AS, the 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 comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 2AS, the 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 comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 3AS, the 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 comprises a nucleoside sequence comprising or consisting of a 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 and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 5AS, the 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 comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 6AS, the 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 comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 7AS, the 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 comprises a nucleoside sequence and an overhang (such as a 3' overhang of 2 bases) and a modification pattern 8AS, the nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NO: 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, the nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NO: 1855-3708 or 13978-13985. In some embodiments, the overhang comprises one or more uridine nucleosides. In some embodiments, one or more uridine nucleosides of the overhang are connected to another nucleoside via a phosphorothioate linker at the 3' end. In some embodiments, the overhang comprises one uridine nucleoside. In some embodiments, the overhang comprises two uridine nucleosides.

[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 an 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 an 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 of 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 1 or 2 nucleotides substituted, added or deleted in NO:2613, 3139, 3434 or 3694.

[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 an 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 an 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 of any one of SEQ ID NOs: 13979-13980 wherein at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having 1 or 2 nucleotide substitutions, additions or deletions of any one of NOs: 13978-13981.

[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: 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 an 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 of any one of SEQ ID NOs: 13986-13987 wherein at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having 1 or 2 nucleotide substitutions, additions or deletions of any one of NOs: 13982-13985.

[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: 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 of any one of SEQ ID NOs: 14134-14157 wherein at least one internucleoside linkage is modified and at least one base is modified. An oligonucleotide sequence having 1 or 2 nucleotide substitutions, additions or deletions of any one of NOs: 14134-14157.

[0145] 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.

[0146] 2. ASO modification mode

[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 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.

[0148] 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 a 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 a sequence of any one of SEQ ID NOs: 3709-13934; or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions; and a modification pattern ASO1. 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 nucleic acid sequence having 3 or 4 nucleoside substitutions, additions or deletions; and a modification pattern ASO1.

[0149] 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.

[0150] D. Preparation

[0151] 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.

[0152] 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.

[0153] II. Methods and Uses

[0154] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject.Some embodiments relate to using a composition described herein, such as administering the composition to a subject.

[0155] Some embodiments relate to methods of treating a condition in a subject in need thereof. Some embodiments relate to the use of a composition as described herein in a method of treatment. Some embodiments include administering a composition as described herein to a subject suffering from a condition. In some embodiments, administering treats a condition in a subject. In some embodiments, the composition treats a condition in a subject.

[0156] 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 a method for preventing, inhibiting or reversing a condition in a subject in need thereof. Some embodiments include 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.

[0157] Some embodiments relate to methods of preventing a condition in a subject in need thereof. Some embodiments relate to the use of a composition as described herein in a method of preventing a condition. Some embodiments include administering a composition as described herein to a subject suffering from a condition. In some embodiments, administration prevents a condition in a subject. In some embodiments, the composition prevents a condition in a subject.

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

[0159] Some embodiments relate to methods of reversing a condition in a subject in need thereof. Some embodiments relate to the use of a composition as described herein in a method of reversing a condition. Some embodiments include administering a composition as described herein to a subject suffering from a condition. In some embodiments, administration reverses the condition of the subject. In some embodiments, the composition reverses the condition of the subject.

[0160] A. Symptoms

[0161] 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 II diabetes). In some embodiments, metabolic conditions include hyperlipidemia. In some embodiments, metabolic conditions include hypertriglyceridemia. In some embodiments, metabolic conditions include familial chylomicronemia. In some embodiments, metabolic conditions include hypertriglyceridemia in the context of familial chylomicronemia. In some embodiments, metabolic conditions include pancreatitis. In some embodiments, metabolic conditions include acute pancreatitis. In some embodiments, metabolic conditions include hypertriglyceridemia and associated acute pancreatitis. In some embodiments, metabolic conditions include diabetes. In some embodiments, metabolic conditions include 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.

[0162] In some embodiments, the disorder is a cardiometabolic disorder, such as a cardiovascular disorder or a metabolic disorder. In some embodiments, the disorder is a cardiovascular disorder. Examples of cardiovascular disorders include heart disease, myocardial infarction, angina (e.g., angina pectoris), and atherosclerosis. In some embodiments, cardiovascular disorders include heart disease. In some embodiments, cardiovascular disorders include myocardial infarction. In some embodiments, cardiovascular disorders include angina pectoris. In some embodiments, cardiovascular disorders include atherosclerosis. Some embodiments include a method of treating a cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL4.

[0163] B. Object

[0164] 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, a mammal, a dog, a cat, a cow, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human.

[0165] In some embodiments, the body mass index (BMI) of the subject is 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.

[0166] 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.

[0167] 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.

[0168] In some embodiments, the subject is 0 to 100 years old. In some embodiments, the subject is 20 to 90 years old. In some embodiments, the subject is 30 to 80 years old. In some embodiments, the subject is 40 to 75 years old. In some embodiments, the subject is 50 to 70 years old. In some embodiments, the subject is 40 to 85 years old.

[0169] C. Baseline Measurements

[0170] 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 treating the subject.

[0171] 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 a 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.

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

[0173] In some embodiments, the baseline cholesterol 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 includes 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, the baseline glucose measurement includes a baseline glucose tolerance test. In some embodiments, the baseline glucose tolerance test includes applying glucose to the object, and then obtaining multiple baseline glucose measurements over time after applying 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) measurements. 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, the baseline glucose measurement includes the baseline glucose measurement in addition to the baseline glucose tolerance test.

[0177] In some embodiments, the baseline measurement is a baseline insulin measurement. In some embodiments, the baseline insulin measurement is a baseline insulin sensitivity measurement. In some embodiments, the baseline insulin sensitivity measurement is obtained using a glucose clamp technique (such as a hyperinsulinemic euglycemic clamp). In some embodiments, the baseline insulin measurement is a baseline insulin concentration. In some embodiments, the baseline insulin measurement includes a baseline insulin concentration. In some embodiments, the baseline insulin measurement is a baseline circulating insulin measurement. In some embodiments, the baseline insulin measurement 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 in addition to a baseline glucose tolerance test.

[0178] In some embodiments, the baseline insulin measurement includes a baseline insulin response test. In some embodiments, the baseline insulin response test includes applying glucose to the object, and then obtaining multiple baseline insulin measurements over time after applying 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 fasting state (such as after an overnight fast).

[0179] In some embodiments, the baseline insulin measurement includes a baseline glucose reaction test. In some embodiments, the baseline glucose reaction test includes administering insulin to the object, and 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, a glucose reaction test is performed on the object in a fasting state (such as after an overnight fast). In some embodiments, the glucose reaction test is performed 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 a 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 within a sample. In some embodiments, the baseline ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total nucleic acid within a sample. In some embodiments, the baseline ANGPTL4 mRNA level is expressed relative to another mRNA level within 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, the baseline measurement is obtained in a sample obtained from a subject. In some embodiments, the sample is obtained from the subject before administering a composition as described herein or treating the subject with a composition as described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject before the composition is administered to the subject. In some embodiments, the sample is obtained from a subject in a fasting state. In some embodiments, the sample is obtained from a subject after an overnight fasting period. In some embodiments, the 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, baseline triglyceride 33 measurements, baseline cholesterol measurements, baseline HDL measurements, baseline glucose measurements, baseline insulin measurements or baseline ANGPTL4 protein measurements 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 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 heart tissue, such as ventricular or atrial tissue. In some embodiments, the sample is a heart sample. In some embodiments, the tissue sample comprises liver, adipose, small intestine, mesenteric lymph node, or heart 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, a 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 is treated. In some embodiments, after the composition is applied to the subject, a measurement is obtained in a second sample (such as a fluid or tissue sample 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 measured value 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, after the composition is administered to the subject, the reduced triglycerides are measured in a second sample obtained from 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, relative to the baseline triglyceride measurement, 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%. 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 the 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 composition reduces cholesterol measurements relative to baseline cholesterol measurements. In some embodiments, the composition reduces circulating cholesterol relative to baseline cholesterol measurements. In some embodiments, after the composition is 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 measurement value, cholesterol 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 cholesterol measurement value, cholesterol measurement value reduces by about 10% or more. In some embodiments, relative to baseline cholesterol measurement value, cholesterol 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 cholesterol measurement value, cholesterol 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 cholesterol measurement value, cholesterol measurement value reduces by no more than about 10%. In some embodiments, relative to baseline cholesterol measurement value, cholesterol measurement value reduces 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 cholesterol 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.

[0196] In some embodiments, the measurement is an HDL measurement. In some embodiments, the HDL measurement is an 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.

[0197] In some embodiments, the composition reduces the HDL measurement relative to the baseline HDL measurement. In some embodiments, the composition increases circulating HDL relative to the baseline HDL measurement. In some embodiments, after the composition is administered to the subject, the increased HDL is measured in a second sample obtained from the subject.

[0198] 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 is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value is increased by no more than about 10% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline HDL measurement value. In some embodiments, the HDL measurement value 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 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.

[0199] 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 determination such as an immunoassay, a colorimetric determination, or a fluorometric determination. In some embodiments, the glucose measured value is obtained using a glucometer.

[0200] In some embodiments, glucose measurement includes a glucose tolerance test. In some embodiments, the glucose tolerance test includes administering glucose to the object, and then obtaining multiple 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 glucose measurements are integrated into glucose area under the curve (AUC) measurements. In some embodiments, a glucose tolerance test is performed on an object in a fasting state (such as after an overnight fast). In some embodiments, glucose measurement includes glucose measurements except the glucose tolerance test.

[0201] In some embodiments, the composition reduces the glucose measurement relative to the baseline glucose measurement. In some embodiments, the composition reduces circulating glucose relative to the baseline glucose measurement. In some embodiments, after the composition is administered to the object, the reduced glucose is measured in a second sample obtained from the object. In some embodiments, the composition reduces one or more of the multiple glucose measurements of the glucose tolerance test relative to one or more of the multiple glucose measurements of the baseline glucose tolerance test. In some embodiments, the composition reduces the glucose AUC measurement relative to the baseline glucose AUC measurement.

[0202] In some embodiments, relative to the baseline glucose measurement value, the glucose measurement value is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more. In some embodiments, relative to the baseline glucose measurement value, the glucose measurement value is reduced by about 10% or more. In some embodiments, relative to the baseline glucose measurement value, 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%. In some embodiments, relative to the baseline glucose measurement value, glucose is 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 glucose measurement value, glucose is reduced by no more than about 10%. In some embodiments, relative to the baseline glucose measurement value, 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%, no more than about 90%, or no more than about 100%. In some embodiments, the glucose 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.

[0203] In some embodiments, the measured value is an insulin measured value. In some embodiments, the insulin measured value is an insulin sensitivity measured value. In some embodiments, the insulin sensitivity measured value is obtained using a glucose clamp technique (such as a hyperinsulinemic euglycemic clamp). In some embodiments, the insulin measured value includes an insulin concentration. In some embodiments, the insulin measured value is an insulin concentration. In some embodiments, the insulin measured value is a circulating insulin measured value. In some embodiments, the insulin measured 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.

[0204] In some embodiments, insulin measurement includes insulin response test. In some embodiments, insulin response test includes applying glucose to the object, then obtaining multiple insulin measurement values ​​over time after applying glucose to the object. In some embodiments, glucose is administered orally. In some embodiments, glucose is administered by injection. In some embodiments, multiple insulin measurement values ​​are integrated into insulin AUC measurement value. In some embodiments, the object in fasting state (such as after overnight fasting) is subjected to insulin response test.

[0205] In some embodiments, insulin measurement includes glucose reaction test. In some embodiments, glucose reaction test includes applying insulin to the object, and then obtaining multiple glucose measurement values ​​over time after applying insulin to the object. In some embodiments, insulin is administered by injection. In some embodiments, multiple glucose measurement values ​​are integrated into glucose AUC measurement value. In some embodiments, multiple glucose measurement values ​​are measured with a blood glucose meter. In some embodiments, glucose reaction test is performed on the object in a fasting state (such as after overnight fasting). In some embodiments, glucose reaction test is performed on the object after applying food, beverage or glucose to the object.

[0206] 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, relative to the baseline insulin sensitivity measurement, insulin sensitivity increases 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 sensitivity measurement, insulin sensitivity increases by no more than about 10%. In some embodiments, relative to the baseline insulin sensitivity measurement, insulin sensitivity 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%. In some embodiments, relative to the baseline insulin sensitivity measurement, insulin sensitivity 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%. 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.

[0207] In some embodiments, the composition reduces insulin measurements relative to baseline insulin measurements. In some embodiments, the composition reduces circulating insulin relative to baseline insulin measurements. In some embodiments, after the composition is administered to the object, the reduced insulin is measured in a second sample obtained from the object. In some embodiments, the composition reduces insulin AUC measurements relative to baseline insulin AUC measurements.

[0208] In some embodiments, relative to the baseline insulin measurement value, the insulin measurement value is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more. In some embodiments, relative to the baseline insulin measurement value, the insulin measurement value is reduced by about 10% or more. In some embodiments, relative to the baseline insulin measurement value, 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%. In some embodiments, relative to the baseline insulin measurement value, insulin is 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 measurement value, insulin is reduced by no more than about 10%. In some embodiments, relative to the baseline insulin measurement value, 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%, no more than about 90%, or no more than about 100%. In some embodiments, the insulin measurement is reduced 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.

[0209] 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 the mass or percentage of ANGPTL4 protein / sample weight. In some embodiments, the ANGPTL4 protein level is expressed as the mass or percentage of ANGPTL4 protein / sample volume. In some embodiments, the ANGPTL4 protein level is expressed as the mass or percentage of ANGPTL4 protein / 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.

[0210] 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.

[0211] 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 the 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.

[0212] 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 within a sample. In some embodiments, the ANGPTL4 mRNA level is expressed as the mass or percentage of ANGPTL4 mRNA per total nucleic acid within a sample. In some embodiments, the ANGPTL4 mRNA level is expressed relative to another mRNA level within a 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. In some embodiments, PCR comprises reverse transcription of ANGPTL4 mRNA.

[0213] 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.

[0214] 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 the baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by about 10% or more relative to the 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 the baseline ANGPTL4 mRNA measurement. 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 the baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is reduced by no more than about 10% relative to the baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline ANGPTL4 mRNA measurement. In some embodiments, the ANGPTL4 mRNA measurement is decreased 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.

[0215] III. Definitions

[0216] 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 those 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 contained herein should not necessarily be construed as representing a substantial difference from what is generally understood in the art.

[0217] Throughout this application, various embodiments can be presented in the form of ranges. It should be understood that the description of the range form is only for convenience and brevity, and should not be interpreted as a hard limit to the scope of the present disclosure. Therefore, the description of the range should be regarded as having all possible sub-ranges disclosed and the individual numerical values ​​within the range. For example, the description of a range such as 1 to 6 should be regarded as having an exact disclosed sub-range, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and the individual numbers within this range, such as 1, 2, 3, 4, 5 and 6. Regardless of the width of the scope, this is applicable.

[0218] 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.

[0219] The terms "determine," "measure," "evaluate," "assess," "measure," 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 may include quantitative, qualitative, or quantitative and qualitative determinations. Assessments may be relative or absolute. In addition to determining whether something is present or absent based on context, "detecting the presence of" may also include determining the amount of something that is present.

[0220] 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 may 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.

[0221] As used herein, the term "about" a number refers to the number 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.

[0222] As used herein, the term "treatment" or "treating" is used to refer 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 benefits may refer to eradicating or improving the underlying condition or its symptoms being treated. In addition, therapeutic benefits may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition so that improvements are 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 progression of a disease or condition, or any combination thereof. For preventive benefits, treatment may be performed on a subject at risk of 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).

[0223] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0224] IV. Sequence Information

[0225] Some embodiments include one or more nucleic acid sequences in the following table:

[0226] Table 1. Sequence information

[0227]

[0228]

[0229] V. Implementation Plan

[0230] Some embodiments include one or more of the following:

[0231] 1. A composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and that lowers circulating triglycerides when administered to a subject in an effective amount.

[0232] 2. The composition of embodiment 1, wherein triglycerides are reduced by about 10% or more as compared to before administration.

[0233] 3. A composition comprising an oligonucleotide that targets ANGPTL4 and reduces circulating total cholesterol when administered to a subject in an effective amount.

[0234] 4. The composition of embodiment 3, wherein the total cholesterol is reduced by about 10% or more as compared to before administration.

[0235] 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.

[0236] 6. The composition of embodiment 5, wherein HDL is increased by about 10% or more as compared to before administration.

[0237] 7. A composition comprising an oligonucleotide that targets ANGPTL4 and that lowers circulating glucose when administered to a subject in an effective amount.

[0238] 8. The composition of embodiment 7, wherein glucose is reduced by about 10% or more as compared to before administration.

[0239] 9. A composition comprising an oligonucleotide that targets ANGPTL4 and increases insulin sensitivity when administered to a subject in an effective amount.

[0240] 10. The composition of embodiment 9, wherein insulin sensitivity is increased by about 10% or more as compared to before administration.

[0241] 11. The composition of any one of embodiments 1-10, wherein the oligonucleotide comprises a modified internucleoside linkage.

[0242] 12. The composition of embodiment 11, wherein the modified internucleoside linkage comprises an alkyl phosphonate, a thiophosphate, a methylphosphonate, a dithiophosphate, an alkyl phosphonothioate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamidate, or a carboxymethyl ester, or a combination thereof.

[0243] 13. The composition of embodiment 11, wherein the modified internucleoside linkage comprises one or more phosphorothioate linkages.

[0244] 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.

[0245] 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, 15 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, In some embodiments, the present invention comprises at least one modified internucleoside linkage, ...

[0246] 16. The composition of any one of embodiments 1-15, wherein the oligonucleotide comprises modified nucleosides.

[0247] 17. A composition as described in 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.

[0248] 18. The composition of embodiment 16, wherein the modified nucleoside comprises LNA.

[0249] 19. The composition of embodiment 16, wherein the modified nucleosides comprise 2',4' constrained ethyl nucleic acids.

[0250] 20. The composition of embodiment 16, wherein 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.

[0251] 21. The composition of embodiment 16, wherein the modified nucleosides include one or more 2' fluorine-modified nucleosides.

[0252] 22. The composition of embodiment 16, wherein the modified nucleosides comprise 2'O-alkyl modified nucleosides.

[0253] 23. The composition of embodiment 16, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 27. The composition of any one of embodiments 1-26, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.

[0258] 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.

[0259] 29. The composition of embodiment 28, wherein the sense strand is 14-30 nucleosides in length.

[0260] 30. The composition of embodiment 28 or 29, wherein the antisense strand is 14-30 nucleosides in length.

[0261] 31. A composition comprising an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a 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.

[0262] 32. A composition comprising an oligonucleotide that inhibits the expression of ANGPTL4, wherein the oligonucleotide comprises a 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.

[0263] 33. The composition of any one of embodiments 28-32, wherein the sense strand and the antisense strand form a double-stranded RNA duplex.

[0264] 34. The composition of embodiment 33, wherein the first base pair of the double-stranded RNA duplex is an AU base pair.

[0265] 35. The composition of any one of embodiments 28-34, wherein the sense strand comprises a 3' overhang comprising 1, 2 or more nucleosides.

[0266] 36. The composition of embodiment 35, wherein the 3' overhang of the sense strand comprises 2 nucleosides.

[0267] 37. The composition of any one of embodiments 28-36, wherein the antisense strand comprises a 3' overhang comprising 1, 2 or more nucleosides.

[0268] 38. The composition of embodiment 37, wherein the 3' overhang of the antisense strand comprises 2 nucleosides.

[0269] 39. A composition as described in any of embodiments 28-38, wherein 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 nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.

[0270] 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.

[0271] 41. A composition as described in any of embodiments 28-40, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of: a sequence of any one of SEQ ID NO: 1855-3708 or 13978-13985; or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.

[0272] 42. The composition of any one of embodiments 28-41, wherein 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.

[0273] 43. The composition of any one of embodiments 28-42, wherein the siRNA binds to the 17-mer in non-human primate ANGPTL4 mRNA.

[0274] 44. The composition of any one of embodiments 28-43, wherein the siRNA binds to the 19-mer in human ANGPTL4 mRNA.

[0275] 45. The composition of any one of embodiments 28-44, wherein the siRNA binds to human ANGPTL4 mRNA and less than or equal to 20 human off-targets with no more than 2 mismatches in the antisense strand.

[0276] 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 (position 2-18) with a minor allele frequency (MAF) greater than or equal to 1%.

[0277] 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, 6 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, 11 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof.

[0278] 48. A composition as described in any 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, 6 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.

[0279] 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 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, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2208, 2209, 2211 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, 269 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. ;

[0280] 50. A composition as described in any 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, 1565 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.

[0281] 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 3014, 3016, 3018, 3019, 3020, 3169, 3197, 3201, 3202, 3283, 3284, 3425, 3426, 3465, 3634, or 3638.

[0282] 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.

[0283] 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, 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. ;

[0284] 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.

[0285] 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.

[0286] 56. A composition as described in any 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, 337, 342, 347, 349 ,353,356,386,388,391,392,394,414,415,422,423,424,426,435,520,5 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 wherein 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, 2010, 2011, 2012, 2013, 2015, 2020, 2023, 2028, 2031, 2050, 2065, 2066, 2071, 2072, 2084, 2085, 2099, 107, 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, 2280 77, 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, 285 6. The nucleotide sequence of any one of 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. ;

[0287] 57. The composition of any one of embodiments 28-56, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 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 wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 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.

[0288] 58. A composition as described in any of embodiments 28-57,...

Claims

1. A composition comprising an oligonucleotide that targets angiopoietin-like 4 (ANGPTL4) and when administered to a subject in an effective amount reduces circulating triglycerides, reduces circulating glucose, increases circulating high-density lipoprotein (HDL), or increases 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 a nucleotide sequence of SEQ ID NO: 13935 and having no more than 2 mismatches, and each strand having 12 to 30 nucleotides.

2. The composition of claim 1, wherein triglycerides, total cholesterol, or glucose is reduced by about 10% or more, or HDL or insulin sensitivity is increased by about 10% or more as compared to before administration.

3. The composition of claim 1, wherein 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.

4. The composition of claim 1, wherein the antisense strand comprises a nucleotide sequence that is at least 85% identical to the antisense strand sequence of the siRNA in Table 4.

5. The composition of claim 1, wherein the antisense strand comprises a nucleotide 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.

6. The composition of claim 1, wherein the antisense strand comprises a nucleotide sequence of the antisense strand sequence of the siRNA in Table 4.

7. The composition of claim 4, wherein the sense strand comprises a nucleotide sequence that is at least 85% identical to the sense strand sequence of the siRNA in Table 4.

8. The composition of claim 4, wherein the sense strand comprises a nucleotide 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.

9. The composition of claim 4, wherein the sense strand comprises a nucleotide sequence of the sense strand sequence of the siRNA in Table 4.

10. A method of treating a metabolic or cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising an oligonucleotide targeting 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 a nucleotide sequence of SEQ ID NO: 13936 and having no more than 2 mismatches, and each strand having 12 to 30 nucleotides.

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