Compositions and methods for inhibiting ANGPTL3 expression
Oligonucleotides are provided herein that inhibit angiopoietin-like protein 3 (ANGPTL3) expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with ANGPTL3 expression.
1 . An RNAi oligonucleotide for reducing angiopoietin-like protein 3 (ANGPTL3) expression, the RNAi oligonucleotide comprising a sense strand forming a duplex region with an antisense strand, wherein:
the sense strand comprises a nucleotide sequence as set forth in sequence: 5′-UCAAAAUGGAAGGUUAUACAGCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 99); and
the antisense strand comprises a nucleotide sequence as set forth in sequence: 5′-UGUAUAACCUUCCAUUUUGAGG-3′ (SEQ ID NO: 100).
2 . The RNAi oligonucleotide of claim 1 , wherein the RNAi oligonucleotide comprises at least one modified nucleotide.
3 . The RNAi oligonucleotide of claim 2 , wherein at least one modified nucleotide comprises a 2′-modification.
4 . The RNAi oligonucleotide of claim 2 , wherein all nucleotides of the oligonucleotide are modified.
5 . The RNAi oligonucleotide of claim 1 , wherein the RNAi oligonucleotide comprises at least one modified internucleotide linkage.
6 . The RNAi oligonucleotide of claim 5 , wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.
7 . The RNAi oligonucleotide of claim 1 , wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog.
8 . The RNAi oligonucleotide of claim 7 , wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate, or malonylphosphonate.
9 . The RNAi oligonucleotide of claim 1 , wherein at least one nucleotide of the RNAi oligonucleotide is conjugated to one or more targeting ligands.
10 . The RNAi oligonucleotide of claim 9 , wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.
11 . The RNAi oligonucleotide of claim 10 , wherein the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.
12 . The RNAi oligonucleotide of claim 11 , wherein up to 4 nucleotides of a stem-loop of the RNAi oligonucleotide are each conjugated to a monovalent GalNAc moiety.
13 . A pharmaceutical composition comprising:
(i) the RNAi oligonucleotide of claim 1 ; and
(ii) a pharmaceutically acceptable carrier, delivery agent, or excipient.
14 . The RNAi oligonucleotide of claim 3 , wherein the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid.
15 . The RNAi oligonucleotide of claim 14 , wherein the 2′-modification is selected from the group consisting of 2′-fluoro (2′-F) and 2′-O-methyl (2′-OMe).
16 . The RNAi oligonucleotide of claim 7 , wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy.
17 . The RNAi oligonucleotide of claim 9 , wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide, or lipid.
18 . The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable carrier comprises water.
19 . The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable carrier comprises phosphate buffered saline.