tailieunhanh - Báo cáo khoa học: Staying on message: design principles for controlling nonspecific responses to siRNA

Short interfering RNAs (siRNA) are routinely used in the laboratory to induce targeted gene silencing by RNA interference, and increasingly, this technology is being translated to the clinic. However, there are multiple mechanisms by which siRNA may be recognized by receptors of the innate immune system, including both endosomal Toll-like receptors and cytoplas-mic receptors. | IFEBS Journal MINIREVIEW Staying on message design principles for controlling nonspecific responses to siRNA Shirley Samuel-Abraham1 and Joshua N. Leonard1 2 1 Department of Chemicaland BiologicalEngineering Northwestern University Evanston IL USA 2 Member Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago IL USA Keywords innate immunity OAS1 off-target RIG-I RNA interference RNAi short interfering RNA siRNA TLR Toll-like receptors Correspondence J. N. Leonard Department of Chemical and BiologicalEngineering Northwestern University 2145 Sheridan Rd Room E-136 Evanston IL 60208 USA Fax 1 847 491 3728 Tel 1 847 491 7455 E-mail j-leonard@ Received 7 July 2010 accepted 26 August 2010 doi Short interfering RNAs siRNA are routinely used in the laboratory to induce targeted gene silencing by RNA interference and increasingly this technology is being translated to the clinic. However there are multiple mechanisms by which siRNA may be recognized by receptors of the innate immune system including both endosomal Toll-like receptors and cytoplasmic receptors. Signaling through these receptors may induce multiple nonspecific effects including general reductions in gene expression and the production of type I interferons and inflammatory cytokines which can lead to systemic inflammation in vivo. The pattern of immune activation varies depending upon the types of cells and receptors that are stimulated by a particular siRNA. Although we are still discovering the mechanisms by which these recognition events occur our current understanding provides useful guidelines for avoiding immune activation. In this minireview we present a design-based approach for developing siRNA-based experiments and therapies that evade innate immune recognition and control nonspecific effects. We describe strategies and trade-offs related to siRNA design considerations including the choice of siRNA target sequence chemical .