title: Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing.
abstract: Transfected siRNAs regulate numerous transcripts sharing limited complementarity to the RNA duplex. This unintended ("off-target") silencing can hinder the use of RNAi to define gene function. Here we describe position-specific, sequence-independent chemical modifications that reduced silencing of partially complementary transcripts by all siRNAs tested. Silencing of perfectly matched targets was unaffected by these modifications. The chemical modification also reduced off-target phenotypes in growth inhibition studies. Key to the modification was 2'-O-methyl ribosyl substitution at position 2 in the guide strand, which reduced silencing of most off-target transcripts with complementarity to the seed region of the siRNA guide strand. The sharp position dependence of 2'-O-methyl ribosyl modification contrasts with the broader position dependence of base-pair substitutions within the seed region, suggesting a role for position 2 of the guide strand distinct from its effects on pairing to target transcripts.
authors: Rosetta Inpharmatics, LLC, Seattle, WA 98109, USA. aimee_jackson@merck.com
authors: Aimee L
authors: AL
authors: Jackson
authors: Julja
authors: J
authors: Burchard
authors: Devin
authors: D
authors: Leake
authors: Angela
authors: A
authors: Reynolds
authors: Janell
authors: J
authors: Schelter
authors: Jie
authors: J
authors: Guo
authors: Jason M
authors: JM
authors: Johnson
authors: Lee
authors: L
authors: Lim
authors: Jon
authors: J
authors: Karpilow
authors: Kim
authors: K
authors: Nichols
authors: William
authors: W
authors: Marshall
authors: Anastasia
authors: A
authors: Khvorova
authors: Peter S
authors: PS
authors: Linsley