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

1 . A method of treating a subject having a cardiovascular or metabolic disorder, comprising administering to the subject a composition comprising an oligonucleotide that targets Angiopoietin like 4 (ANGPTL4) and decreases ANGPTL4 expression in the subject, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand comprises 5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′ (modification pattern 6AS), wherein “N” comprises one or more nucleosides, “Nf”′ is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

2 . The method of claim 1 , wherein the sense strand or antisense strand comprises a modified nucleoside.

3 . The method of claim 2 , wherein the modified nucleoside comprises a 2′-fluoro modified nucleoside.

4 . The method of claim 2 , wherein the modified nucleoside comprises a 2′-O-methyl modified nucleoside.

5 . The method of claim 2 , wherein the sense strand comprises 15-23 modified nucleosides.

6 . The method of claim 5 , wherein the 15-23 modified nucleosides comprises 2′-fluoro modified nucleosides and 2′-O-methyl modified nucleosides.

7 . The method of claim 1 , wherein the sense strand comprises a modified internucleoside linkage.

8 . The method of claim 7 , wherein the modified internucleoside linkage comprises a phosphorothioate linkage.

9 . The method of claim 1 , wherein the composition comprises an N-acetylgalactosamine (GalNAc) ligand.

10 . The method of claim 9 , wherein the GalNAc ligand comprises 3 GalNAc moieties.

11 . The method of claim 9 , wherein the GalNAc ligand is attached to the oligonucleotide at a 5′ or 3′ terminus of the sense strand.

12 . The method of claim 1 , wherein the sense strand or the antisense strand comprises a 3′ overhang.

13 . The method of claim 1 , wherein the sense strand or the antisense strand comprises any of the following modification patterns:

5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13954, modification pattern 1S),

5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13955, modification pattern 2S),

5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′ (SEQ ID NO: 13956, modification pattern 3S),

5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3′ (SEQ ID NO: 13957, modification pattern 4S),

5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3′ (SEQ ID NO: 13958, modification pattern 5S), or

5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′ (SEQ ID NO: 13959, modification pattern 6S),

wherein “N” comprises one or more nucleosides, “Nf” is a 2′ fluoro-modified nucleoside, “n” is a 2′ O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

14 . The method of claim 1 , wherein the sense strand comprises the oligonucleotide sequence of any of SEQ ID NOS: 13970-13977, or the antisense strand comprises the oligonucleotide sequence of any of SEQ ID NOS: 13978-13985 or

wherein the sense strand comprises an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any of 13970-13977, or the antisense strand comprises an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of any of SEQ ID NOS: 13978-13985.

15 . The method of claim 1 , wherein the administration treats the cardiovascular or metabolic disorder.

16 . The method of claim 15 , wherein the administration decreases a measurement of a cardiovascular or metabolic disorder parameter by at least 10% in the subject, relative to a baseline measurement.

17 . The method of claim 1 , wherein the cardiovascular disorder comprises heart disease, myocardial infarction, angina pectoris, or atherosclerosis.

18 . The method of claim 1 , wherein the metabolic disorder comprises hypertriglyceridemia, diabetes, type 2 diabetes, or hyperlipidemia.