Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.
1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ANGPTL3, or a salt thereof,
wherein said dsRNA, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
a) wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-ACAUAUAAACUACAAGUCAAA-3′ of SEQ ID NO:296 and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UUUGACUUGUAGUUUAUAUGUAG-3′ of SEQ ID NO: 481;
b) wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-CUAGAGAAGAUAUACUCCA-3′ of SEQ ID NO:24 and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UGGAGUAUAUCUUCUCUAG-3′ of SEQ ID NO:86;
c) wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-AAUCAAGAUUUGCUAUGUU-3′ of SEQ ID NO:23 and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-AACAUAGCAAAUCUUGAUU-3′ of SEQ ID NO:85;
d) wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-CACUUGAACUCAACUCAAA-3′ of SEQ ID NO:21 and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UUUGAGUUGAGUUCAAGUG-3′ of SEQ ID NO:83; or
e) wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UAUUUGAUCAGUCUUUUUA-3′ of SEQ ID NO: 16 and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UAAAAAGACUGAUCAAAUA-3′ of SEQ ID NO:78.
2 . The dsRNA, or a salt thereof, of claim 1 , wherein at least one nucleotide of the dsRNA, or a salt thereof, comprises a nucleotide modification.
3 . The dsRNA, or a salt thereof, of claim 2 , wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-deoxy-2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, and a non-natural base comprising nucleotide modification.
4 . The dsRNA, or a salt thereof, of claim 1 , wherein each strand is independently no more than 30 nucleotides in length.
5 . The dsRNA, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least one strand comprises a 3′ overhang of at least 2 nucleotides.
6 . The dsRNA, or a salt thereof, of claim 1 , further comprising a ligand.
7 . The dsRNA, or a salt thereof, of claim 6 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.
8 . The dsRNA, or a salt thereof, of claim 6 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
9 . The dsRNA, or a salt thereof, of claim 8 , wherein the ligand is
10 . An isolated cell containing the dsRNA, or a salt thereof, of claim 1 .
11 . A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene comprising the dsRNA, or a salt thereof, of claim 1 .
12 . The pharmaceutical composition of claim 11 , further comprising a lipid formulation.
13 . The dsRNA, or a salt thereof, of claim 1 , further comprising at least one phosphorothioate or methylphosphonate internucleotide linkage.