Antisense oligonucleotide knock-down of ataxin-7 in a SCA7 mouse model
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DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder that results in a cone- rod dystrophy form of retinal degeneration. The mutation inherited by SCA7 patients is a CAG / polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. The SCA7 mutation results in the production of a toxic polyQ-expanded ataxin-7 protein. Since the expression of the toxic gene product drives all subsequent disease pathology in SCA7 and related polyQ disorders, the most attractive therapeutic paradigm for these diseases is to terminate the expression of the mutant gene product. Here we propose a translational research program intended to yield therapeutic agents for SCA7 retinal degeneration. We will pursue ataxin-7 "gene silencing" using a therapeutic strategy that has already been successfully applied to achieve reduced expression of a toxic protein: antisense oligonucleotide (ASO) knock-down. To achieve the goals of this translational research program, we have created an academic-industrial partnership. For ASO knock-down, we will work with ISIS Pharmaceuticals, a company that specializes in ASO production, having successfully developed an ASO therapy for CMV retinitis. Working with ISIS, we have already generated leads that effectively knock-down ataxin-7 in pilot studies. As the PI's group has developed mouse models that accurately recapitulate the cone-rod dystrophy phenotype observed in human SCA7 patients, and has worked with a similar SCA7 knock-in mouse model, we will employ a series of behavioral, histological and molecular studies to determine the efficacy of these treatment strategies in preclinical trials. If our preclinical trial work reveals that ataxin7 gene silencing is a safe and effective therapy for SCA7 retinal degeneration, then we will proceed to lead optimization and IND-enabling studies in the next stage of this project, as a prelude to a clinical trial in human SCA7 patients.
