EP3913056A1 — Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases

USPTO Abstract

The present invention relates to a double stranded RNAi agent comprising a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region substantially complementary to nucleotides 504 to 526 of the transthyretin (TTR) gene of SEQ ID NO: 1, wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length, wherein said double stranded RNAi agent comprises the sense strand represented by the following formula (I): 5' n p -N a -(X X X) i -N b -Y Y Y -N b -(Z Z Z) j -N a - n q 3' (I) wherein: i is 1 and j is 0; or i is 0 and j is 1; or both i and j are each independently 0 or 1; p and q are each independently 0-6; each N a independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; each N b independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; each n p and n q independently represents an overhang nucleotide; XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides; modifications on N b differ from the modification on Y; wherein YYY is all 2'-F modified nucleotides; and wherein the sense strand is conjugated to at least one ligand, wherein the ligand is a Ga1NAc ligand at 3' end.