Immune activation by siRNA/liposome complexes in mice is sequence- independent: lack of a role for toll-like receptor 3 signaling

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Title
Immune activation by siRNA/liposome complexes in mice is sequence- independent: lack of a role for toll-like receptor 3 signaling
Author(s)
J Y Kim; S Choung; E J Lee; Young Joo Kim; Y C Choi
Bibliographic Citation
Molecules and Cells, vol. 24, no. 2, pp. 247-254
Publication Year
2007
Abstract
Improvement in the pharmacokinetic properties of short interfering RNAs (siRNAs) is a prerequisite for the therapeutic application of RNA interference technology. When injected into mice as unmodified siRNAs complexed to DOTAP/Chol-based cationic liposomes, all 12 tested siRNA duplexes caused a strong induction of cytokines including interferon α, indicating that the immune activation by siRNA duplexes is independent of sequence context. When modified by various combinations of 2′-OMe, 2′-F, and phosphorothioate substitutions, introduction of as little as three 2′-OMe substitutions into the sense strand was sufficient to suppress immune activation by siRNA duplexes, whereas the same modifications were much less efficient at inhibiting the immune response of single stranded siRNAs. It is unlikely that Toll-like receptor 3 (TLR3) signaling is involved in immune stimulation by siRNA/liposome complexes since potent immune activation by ds siRNAs was induced in TLR3 knockout mice. Together, our results indicate that chemical modification of siRNA provides an effective means to avoid unwanted immune activation by therapeutic siRNAs. This improvement in the in vivo properties of siRNAs should greatly facilitate successful development of siRNA therapeutics.
Keyword
chemical modificationimmune activationsiRNAtoll-like receptor 3
ISSN
1016-8478
Publisher
South Korea
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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