SiRNA sequence-independent modification formats for reducing off-target phenotypic effects in RNAi, and stabilized forms thereof

摘要

Modification formats having modified nucleotides are provided for siRNA. Short interfering RNA having modification formats and modified nucleotides provided herein reduce off-target effects in RNA interference of endogenous genes. Further modification formatted siRNAs are demonstrated to be stabilized to nuclease-rich environments. Unexpectedly, increasing or maintaining strand bias, while necessary to maintain potency for endogenous RNA interference, is not sufficient for reducing off-target effects in cell biology assays.

主权项

1. A short interfering RNA, comprising:
a passenger oligonucleotide having a length of 21 nucleotides and consisting of a modification format wherein nucleotides 1, 2, 13, 14, and at least two of nucleotides 18, 19, 20 and 21 are modified wherein nucleotides are numbered from the 5′ end, and a guide oligonucleotide having 21 nucleotides, a region of continuous complementarity to the passenger oligonucleotide of at least 12 nucleotides, complementarity to at least a portion of target mRNA, and comprising a modification format wherein nucleotides 20 and 21 are modified wherein nucleotides are numbered from the 5′ end, wherein each modified nucleotide is independently a bicyclonucleotide, a tricyclonucleotide, or a 2′-modified nucleotide.