The many recent reports documenting the therapeutic efficacy of short interfering RNAs (siRNAs) in animal models of human disease may actually be describing non-specific therapeutic effects related to the ability of siRNA to activate an immune response, according to a new paper.
Authors Marjorie Robbins, Adam Judge, Ellen Ambegia, Catherine Choi, Ed Yaworski, Lorne Palmer, Kevin McClintock, and Ian MacLachaln of Protiva Biotherapeutics (Burnaby, BC Canada) emphasize the need for researchers to design siRNA studies that incorporate suitable controls to differentiate the disease-modulating effect of an siRNA from its ability to stimulate an innate immune response.
siRNAs have been highly touted for their ability to target very specifically and selectively the disease-causing factors in a range of disorders, from viral infections to tumors and inflammatory and immunologic processes. However, siRNA also has the potential to activate innate immunity and the production of interferons, which can in turn bring about therapeutic effects in a range of disease models.
The authors of this paper contend that, "surprisingly few of the reported studies have adequately tested, or controlled, for the potential effects of siRNA-mediated immune stimulation."
In the current study, use of a commonly used control siRNA sequence called GFP siRNA, which has only a minimal capacity to activate the immune system, clearly showed the striking difference between the immunostimulatory potential of GFP siRNA and of some other siRNAs. Using a mouse model of influenza, the authors demonstrated that the anti-viral activity of siRNA is mainly due to non-specific stimulation of the immune system rather than to a targeted attack on the disease-causing virus.
"siRNA holds tremendous potential as a research tool, however its clinical development is still in its infancy. The study by Robbins et al. points out a very important issue regarding non-specific effects that should be considered when designing and evaluating siRNA strategies," says James M. Wilson, MD, PhD, Editor-in-Chief, and Head of the Gene Therapy Program, Division of Medical Genetics, University of Pennsylvania School of Medicine, in Philadelphia.
- Robbins et al. Misinterpreting the therapeutic effects of siRNA caused by immune stimulation. Human Gene Therapy, 2008; 0 (ja): 080819061428278 DOI: 10.1089/hgt.2008.131
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