Rational design of immunostimulatory siRNAs

Gantier, Michael P., Tong, Stephen, Behlke, Mark A., Irving, Aaron T., Lappas, Martha, Nilsson, Ulrika W., Latz, Eicke, McMillan, Nigel A. J. and Williams, Bryan R. G. (2010) Rational design of immunostimulatory siRNAs. Molecular Therapy, 18 4: 785-795. doi:10.1038/mt.2010.4

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Author Gantier, Michael P.
Tong, Stephen
Behlke, Mark A.
Irving, Aaron T.
Lappas, Martha
Nilsson, Ulrika W.
Latz, Eicke
McMillan, Nigel A. J.
Williams, Bryan R. G.
Title Rational design of immunostimulatory siRNAs
Journal name Molecular Therapy   Check publisher's open access policy
ISSN 1525-0016
Publication date 2010-04
Sub-type Article (original research)
DOI 10.1038/mt.2010.4
Open Access Status File (Author Post-print)
Volume 18
Issue 4
Start page 785
End page 795
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2011
Language eng
Subject 0601 Biochemistry and Cell Biology
0604 Genetics
Abstract Short-interfering RNAs (siRNAs) have engendered much enthusiasm for their ability to silence the expression of specific genes. However, it is now well established that siRNAs, depending on their sequence, can be variably sensed by the innate immune system through recruitment of toll-like receptors 7 and 8 (TLR7/8). Here, we aimed to identify sequence-based modifications allowing for the design of bifunctional siRNAs with both proinflammatory and specific silencing activities, and with potentially increased therapeutic benefits. We found that the introduction of a micro-RNA (miRNA)-like nonpairing uridine-bulge in the passenger strand robustly increased immunostimulatory activity on human immune cells. This sequence modification had no effect on the silencing efficiency of the siRNA. Increased immunostimulation with the uridine-bulge design was specific to human cells, and conserved silencing efficiency required a Dicer-substrate scaffold. The increased cytokine production with the uridine-bulge design resulted in enhanced protection against Semliki Forest virus (SFV) infection, in viral assays. Thus, we characterize a design scaffold applicable to any given siRNA sequence, that results in increased innate immune activation without affecting gene silencing. Our data suggest that this sequence modification coupled with structural modification differentially recruits human TLR8 over TLR7, and could have potential application in antiviral therapies.
Keyword Small interfering RNA
Chronic hepatitis-B
In-vivo delivery
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 37 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 41 times in Scopus Article | Citations
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Created: Sun, 02 May 2010, 00:02:54 EST