Oligonucleotides for treatment of angiopoietin like 4 (ANGPTL4) related diseases
Provided are compositions comprising an oligonucleotide that targets Angiopoietin-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 that targets ANGPTL4 to a subject in need thereof.
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.