Research Grant Award

Henry Paulson, MD, PhD

University of Michigan, Ann Arbor, MI
RNAi as therapy for spinocerebellar ataxia type 3 (SCA3)

Spinocerebellar Ataxia type 3 is a dominantly inherited form of ataxia for which currently there is no cure. Because the disorder is caused by a "toxic" disease protein, turning off production of the disease protein is a promising route to therapy. We propose to exploit the power of RNA interference (RNAi) to silence the disease gene (ATXN3) in a mouse model of SCA3. The mouse model we have chosen expresses the full human ATXN3 gene with its normal promoter, making it as close to the human situation as we can get at this time. We and others have already proven that RNAi can suppress the expression of disease-causing genes, as in SCA3. Our goal here is not to reinvent the wheel but instead to take advantage of our lab's expertise in RNAi and in SCA3, our demonstrated commitment to this disease, and our experience with this mouse model to carry out necessary preclinical studies that are desperately needed if RNA is ever to be brought to the clinic for patients with SCA3. Our studies will create two different RNAi reagents targeting different regions in the disease gene; both will be expressed via engineered viruses that can efficiently be delivered to the brain and result in sustained “knock-down” of the targeted disease gene. If the studies are successful, we will be well-positioned to go forward with second phase preclinical studies which are longer term and beyond the scope of the current one year proposal. Completion of the currently proposed studies will allow us to compete successfully for federal funding to continue the work and, we hope eventually, bring RNAi to the SCA3 clinic.