DOUBLE-CHAIN ​​RIBONUCLEIC ACID MOLECULE (RNAi) ISOLATED TO INHIBIT THE EXPRESSION OF PNPLA3, OR A SALT THEREOF

Abstract

RNAi agents, for example, double-stranded RNAi agents, targeting a gene containing a patatin-like phospholipase 3 (PNPLA3) domain, and methods of using such RNAi agents to inhibit the expression of a PNPLA3 gene, and methods of treating subjects with non-alcoholic fatty liver disease (NAFLD) and / or a PNPLA3-associated disorder.

Claims

1. An isolated double-stranded ribonucleic acid (RNAi) molecule for inhibiting PNPLA3 expression, or a salt thereof, characterized in that the double-stranded RNAi molecule, or salt thereof, comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises 16 contiguous nucleotides of the 5'-ACCCAUUAGGAUAAUGUCU-3' nucleotide sequence of SEQ ID NO: 312 and the antisense strand comprises 18 contiguous nucleotides of the 5'-AGACAUUAUCCUAAUGGGU-3' nucleotide sequence of SEQ ID NO: 563, all nucleotides of the sense strand comprising a nucleotide modification selected from the group consisting of a 2'-O-methyl nucleotide modification and a 2'-fluorine nucleotide modification, the sense strand comprising two internucleotide phosphorothioate linkages at the 5' end,All nucleotides of the antisense strand comprise a nucleotide modification selected from the group consisting of a 2'-O-methyl nucleotide modification and a 2'-fluorine nucleotide modification; the antisense strand comprises two phosphorothioate internucleotide bonds at the 5' end and two phosphorothioate internucleotide bonds at the 3' end; each strand is independently 21-23 nucleotides in length; and the sense strand is conjugated to a GalNAc ligand, which is (FORMULA 1). Six claims follow.