Journal article
Rational design of immunostimulatory siRNAs
MP Gantier, S Tong, MA Behlke, AT Irving, M Lappas, UW Nilsson, E Latz, NAJ McMillan, BRG Williams
Molecular Therapy | Published : 2010
DOI: 10.1038/mt.2010.4
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 imm..
View full abstractRelated Projects (1)
Grants
Awarded by National Health and Medical Research Council
Funding Acknowledgements
We are grateful to Scott Rose ( Integrated DNA Technologies) for his help in the production of the RNA oligonucleotides, Paul Cameron and Vanessa Evans (Monash University, Department of Medicine, Alfred Campus, Melbourne, Australia) for their help in the purification of human monocytes, Die Wang (Monash Institute of Medical Research) for the recombinant GFP, Anthony Sadler ( Monash Institute of Medical Research) for the HEK 293T-GFP cells and Ashley Mansell ( Monash Institute of Medical Research) for his assistance with SeV infections. This work is supported by funding from the Australian NHMRC 491106, The Arthur Wilson Fellowship from The RANZCOG Research Foundation, and the Victorian Government's Operational Infrastructure Support Program. S. T. is supported by an NHMRC Career Development Award ( 490970). M. A. B. is employed by Integrated DNA Technologies, which offers oligonucleotides for sale similar to some of the compounds described in the article. Integrated DNA Technologies (IDT) is, however, not a publicly traded company, and he does not own any shares or hold equity in IDT. M. P. G., S. T., and B. R. G. W. are the inventors of the Monash University international (PCT) patent application PCT/AU2009/000175, entitled Immunostimulatory siRNA Molecules.