RNAi-Based Therapy of ALS

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RNA interference (RNAi) is a widespread gene-silencing phenomenon initiated by a double-stranded RNA that is converted into small interfering RNAs (siRNAs). Although the detailed mechanism whereby siRNA silences its target gene expression is not understood, it has been well established that siRNA associates with an RNAinduced silencing complex (RiSe) to form an RNA-protein complex that can recognize and cleave an mRNA target that complements the siRNA sequence. We would like to understand the rules for chemical modifications of siRNA to enhance the stability and delivery of these molecules for efficient gene silencing in vivo. One of the great potential applications of RNAi-based therapy is to control disease states caused by dominant, gain of function mutations in people bearing one wild-type and one mutant copy of the gene. Some of the best known examples of such diseases are neurodegenerative diseases including Huntingtqn's, a subset of amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's diseases. Although the exact functional pathways delineating how the mutant proteins cause cell degeneration are not entirely clear, the origin of the cellular toxicity is known to be the mutant proteins in these neurodegenerative diseases. We reason that RNAi could be employed to reduce the mutant protein concentrations and thereby slow or block the progression of neurodegenerative diseases. The effectiveness of RNAi in slowing down the ALS progression has been demonstrated in vivo using transgene delivered RNAi. However, the transgene-based delivery has problems in clinical application. In this proposal, we focus on developing siRNA as small molecule drugs. We propose to develop and test chemically modified, stabilized, cell-permeable and silencing competent siRNA in treatment of ALS animal models that express mutant Cu, Zn superoxide dismutase (SOD1). Findings of proposed research will also offer a new perspective important in developing RNAi-based therapies for other neurodegenerative diseases.