EP4585686A2 — Modified double-stranded rna agents

USPTO Abstract

The present invention relates to a double-stranded RNA (dsRNA) capable of inhibiting the expression of a target gene, comprising: (a) a sense strand having: (i) a length of 21 nucleotides; (ii) an asialoglycoprotein receptor (ASGPR) ligand attached to the 3'-end, wherein said ASGPR ligand comprises three N-acetyl-galactosamine (GalNAc) derivatives attached through a trivalent branched linker; (iii) 2'-OMe modifications at positions 1 to 6, 8, and 12 to 21, and 2'-F modifications at positions 7, and 9 to 11, counting from the 5'-end of the sense strand; and (iv) phosphorothioate internucleotide linkages between nucleotide positions 1 and 2, and between nucleotide positions 2 and 3, counting from the 5' end of the sense strand; and (b) an antisense strand having (i) a length of 23 nucleotides; (ii) 2'-OMe modifications at positions 1, 3 to 5, 7, 8, 10 to 13, 15, and 17 to 23, and 2'-F modifications at positions 2, 6, 9, 14, and 16, counting from the 5' end of the antisense strand; and (iii) phosphorothioate internucleotide linkages between nucleotide positions 1 and 2, between nucleotide positions 2 and 3, between nucleotide positions 21 and 22, and between nucleotide positions 22 and 23, each counting from the 5' end of the antisense strand; wherein the dsRNA has a two nucleotide overhang at the 3'-end of the antisense strand, and a blunt end at the 5'-end of the antisense strand.