Research Grant Award

Robert Wilson, MD, PhD

University of Pennsylvania School of Medicine, Philadelphia, PA
RNAi therapeutics for Friedreich's ataxia

Current therapeutic initiatives for Friedreich's ataxia comprise the screening and/or testing of conventional chemical compounds – to increase the expression of frataxin, to mitigate or reverse the deleterious effects of decreased frataxin expression on cellular energy production, or to reverse the subcellular iron accumulation that apparently contributes to the signs and symptoms of the disorder. The purpose of the experiments described in this proposal is to identify therapeutics for Friedreich’s ataxia using an alternative, and completely novel, approach. This approach is a selection screen for therapeutics based on what is called RNA interference (RNAi). RNAi is a recently discovered mechanism by which cells regulate gene expression, and which can be exploited for therapeutic purposes. Although delivery issues for RNAi therapeutics are still being worked out (i.e., how to get RNAi constructs into particular cell types), several companies are already involved in clinical trials of RNAi therapeutics, including Acuity (age-related macular degeneration, diabetic retinopathy), Alnylam (respiratory syncytial virus), and Sirna (age-related macular degeneration, hepatitis C). For this proposal, we will put several hundred thousand separate RNAi sequences into several hundred thousand cells (in a tissue culture flask) from an individual with Friedreich's ataxia. We will then select cells that thrive under conditions normally deleterious to Friedreich's ataxia cells and retrieve the RNAi sequences that allow the cells to thrive. (In effect, we let the cells to tell us which sequences work best.) Through an iterative process of varying the most beneficial sequences, re-screening the variants in cells, and retrieving those that are even more beneficial, we will optimize RNAi sequences as potential therapeutics for Friedreich's ataxia. We will partner with one or more of the companies involved in RNAi therapeutics to bring the best sequences into clinical development. Although this proposal focuses on Friedreich's ataxia, the experiments will serve as a proof-of-principal for a similar approach to identifying RNAi therapeutics for the dominant ataxias.