EP3812462A1 — Modified double-stranded rna agents

USPTO Abstract

The present invention relates to a double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 40 nucleotides, wherein the dsRNA agent is represented by formula (I):wherein:B1, B1', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-Oalkyl, 2'-substituted alkoxy, 2'-substituted alkyl, 2'-halo, ENA, and BNA/LNA; B2 and B3 each contain 2'-OMe modifications;C1 is a thermally destabilizing nucleotide placed at a site opposite to positions 2-8 of the 5'-end of the antisense strand;T1, T1', T2', and T3' each independently represent a nucleotide comprising a modification providing the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2'-OMe modification;each n<sup>1</sup>, n<sup>3</sup>, and q<sup>1</sup> is independently 4 to 15 nucleotides in length;each n<sup>5</sup>, q<sup>3</sup>, and q<sup>7</sup> is independently 1-6 nucleotide(s) in length;each q<sup>2</sup> and q<sup>6</sup> is independently 1-3 nucleotide(s) in length;q<sup>5</sup> is independently 0-10 nucleotide(s) in length; andeach n<sup>2</sup>, n<sup>4</sup>, and q<sup>4</sup> is independently 0-3 nucleotide(s) in length.