Soon after Tuschl and colleagues demonstrated that RNA interference (RNAi) operates in mammalian cells via short RNA duplexes of 19 to 23 nucleotides in length,1 tremendous efforts were taken to study the feasibility of this new technique to treat human disease. RNAi has been shown to mediate specific and effective gene silencing. The specificity and effectiveness, coupled with the fact that every animal gene can potentially be targeted via this mechanism, suggest that this technique may provide an exciting new therapeutic tool with a wide array of potential disease targets.2 However, two recent reports suggest that siRNAs, particularly at high concentrations, may also silence genes with incomplete homology and induce an interferon (IFN) response with global inhibition of translation. These off-target effects may lead to toxicity and need to be considered in all in vivo experiments. Induction of an IFN response is likely to be more of an issue when RNAi is induced via viral vectors.3,4
To date, most studies investigating RNAi in mammalian cells have been carried out in vitro, often using transformed cell lines, which may have different properties than primary cells. However, this year, the first report to apply RNAi to an animal disease model was published.5 In this study, hydrodynamically injected duplex siRNA directed against Fas effectively silenced endogenous gene expression for 10 days without diminution, and mice with silenced Fas expression were protected from hepatic destruction, and death in two models of autoimmune hepatitis. Thereafter, RNAi-based therapies have been implemented in a variety of animal disease models, including viral and autoimmune hepatitis,6,7 septic shock,8 cancer,9,10 ocular neovascularization,11
and neurodegenerative disease.12 So far, mice are the only mammalian models for which RNAi has been reported.