Jul 09, 2007
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My research program focuses on modulating gene expression in vivo with the goal of developing a treatment for dominant genetic disease of muscle. My laboratory team seeks to employ an endogenous cell mechanism for fine-tuning gene expression at the post-transcriptional level, referred to as the RNA interference (RNAi). RNAi is triggered by processing of double-stranded RNA for sequence-specific gene silencing through direct base pairing with the target mRNA. Development of RNAi expression cassettes targeting mRNAs that lead to dominant genetic disease in muscle is a main focus of the laboratory. Both high expression level ubiquitous promoters and tissue-specific promoters are incorporated into adeno-associated virus vectors (AAV) to drive double-stranded RNA hairpin expression to carry out targeted RNAi. AAV-mediated tissue tropism combined with variations in muscle promoter-dependent expression are used to fine-tune therapeutic RNAi delivery. The RNAi expression vectors are tested both in cell cultures and in pre-clinical disease models, with the ultimate goal of preventing the effects of unwanted gene expression leading to human disease.
The dominant muscular dystrophies that we are studying are facioscapulohumeral muscular dystrophy (FSHD) and myotonic dystrophy (DM), the 2 most common adult muscular dystrophies with a combined prevalence of approximately 1:2400 individuals. Although FSHD and DM are clinically distinct movement disorders, both diseases are caused by genetic defects that lead to production of toxic cell products that can be targeted by RNAi for destruction. Our challenge is to couple timely intervention with a safe and effective therapy. As we learn more about these diseases and the details of the RNAi pathway, we are better able to show feasibility of this approach in complex living organisms. Recent progress in reversing disease in the FRG1 model of FSHD demonstrates proof-of-principle and we are refining this approach for the ultimate goal of producing a therapy for treating dominant genetic disease of muscle and, in general, for treating disease by modulation of gene expression.