Patatin-like phospholipase domain containing 3 (PNPLA3) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Patatin-Like Phospholipase Domain Containing 3 (PNPLA3) gene, and methods of using such RNAi agents to inhibit expression of a PNPLA3 gene and methods of treating subjects having Nonalcoholic Fatty Liver Disease (NAFLD) and/or a PNPLA3-associated disorder.
1 . A double stranded ribonucleic acid (RNAi) agent, or a salt thereof, for inhibiting expression of Patatin-Like Phospholipase Domain Containing 3 (PNPLA3), wherein said double stranded RNAi agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UUUGGAAUGGAACUCAGACACCA-3′ of SEQ ID NO: 1370 or 5′-UUAAACAUUAUUUUAGUUAGGUG-3′ of SEQ ID NO: 1362.
2 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein at least one nucleotide of the double stranded RNAi agent comprises a nucleotide modification.
3 . The double stranded RNAi agent, or a salt thereof, of claim 2 , wherein the nucleotide modification is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl-nucleotide modification, 2′-C-alkyl-nucleotide modification, 2′-hydroxylnucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate nucleotide modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification e, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, and a nucleotide comprising a 5′-phosphate mimic modification.
4 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the duplex region is about 15-30 nucleotides in length.
5 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least 2 nucleotides.
6 . The double stranded RNAi agent, or a salt thereof, of claim 1 , further comprising a ligand.
7 . The double stranded RNAi agent, or a salt thereof, of claim 6 , wherein the ligand is one or more N-acetylgalactosamine (GalNAc) derivatives.
8 . The double stranded RNAi agent, or a salt thereof, of claim 7 , wherein the ligand is
9 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein said double stranded RNAi agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
10 . An isolated cell containing the double stranded RNAi agent, or a salt thereof, of claim 1 .
11 . A pharmaceutical composition for inhibiting expression of a PNPLA3 gene comprising the double stranded RNAi agent, or a salt thereof, of claim 1 .
12 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5′-UUUGGAAUGGAACUCAGACACCA-3′ of SEQ ID NO: 1370.
13 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-UUUGGAAUGGAACUCAGACACCA-3′ of SEQ ID NO: 1370.
14 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UUUGGAAUGGAACUCAGACACCA-3′ of SEQ ID NO: 1370.
15 . The double stranded ribonucleic acid (RNAi) agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UUUGGAAUGGAACUCAGACACCA-3′ of SEQ ID NO: 1370, and wherein the sense strand comprises the nucleotide sequence 5′-GUGUCUGAGUUCCAUUCCAAA-3′ of SEQ ID NO: 1280.
16 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5′-UUAAACAUUAUUUUAGUUAGGUG-3′ of SEQ ID NO: 1362.
17 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-UUAAACAUUAUUUUAGUUAGGUG-3′ of SEQ ID NO: 1362.
18 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 20 contiguous nucleotides from the nucleotide sequence 5′-UUAAACAUUAUUUUAGUUAGGUG-3′ of SEQ ID NO: 1362.
19 . The double stranded RNAi agent, or salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UUAAACAUUAUUUUAGUUAGG-3′ of SEQ ID NO: 1362, and wherein the sense strand comprises the nucleotide sequence 5′-CCUAACUAAAAUAAUGUUUAA-3′ of SEQ ID NO: 1272.
20 . The double stranded RNAi agent, or a salt thereof, of claim 5 , wherein the 3′ overhang is present in the antisense strand.
21 . The double stranded RNAi agent, or a salt thereof, of claim 9 , wherein the at least one phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.
22 . The double stranded RNAi agent, or a salt thereof, of claim 21 , wherein the strand is the antisense strand.
23 . The double stranded RNAi agent, or a salt thereof, of claim 9 , wherein the at least one phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.
24 . The double stranded RNAi agent, or a salt thereof, of claim 23 , wherein the strand is the antisense strand.
25 . The double stranded RNAi agent, or a salt thereof, of claim 23 , wherein the strand is the sense strand.
26 . The double stranded RNAi agent, or a salt thereof, of claim 9 , wherein the at least one phosphorothioate or methylphosphonate internucleotide linkage is at both the 5′- and 3′-terminus of one strand.