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Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs.

Abstract：

:siRNAs confer sequence specific and robust silencing of mRNA. By virtue of these properties, siRNAs have become therapeutic candidates for disease intervention. However, their use as therapeutic agents can be hampered by unintended off-target effects by either or both strands of the siRNA duplex. We report here that unlocked nucleobase analogs (UNAs) confer desirable properties to siRNAs. Addition of a single UNA at the 5'-terminus of the passenger strand blocks participation of the passenger strand in RISC-mediated target down-regulation with a concomitant increase in guide strand activity. Placement of a UNA in the seed region of the guide strand prevents miRNA-like off-target silencing without compromising siRNA activity. Most significantly, combined substitution of UNA at the 3'-termini of both strands, the addition of a UNA at the 5'-terminus of the passenger strand, and a single UNA in the seed region of the guide strand, reduced the global off-target events by more than 10-fold compared to unmodified siRNA. The reduction in off-target events was specific to UNA placement in the siRNA, with no apparent new off-target events. Taken together, these results indicate that when strategically placed, UNA substitutions have important implications for the design of safe and effective siRNA-based therapeutics.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Vaish N,Chen F,Seth S,Fosnaugh K,Liu Y,Adami R,Brown T,Chen Y,Harvie P,Johns R,Severson G,Granger B,Charmley P,Houston M,Templin MV,Polisky B

doi

10.1093/nar/gkq961

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

1823-32

issue

5

eissn

0305-1048

issn

1362-4962

pii

gkq961

journal_volume

39

pub_type

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