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.

Public Health Relevance

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder in which patients develop a cone-rod dystrophy form of retinal degeneration, caused by CAG / polyglutamine repeat expansions in the ataxin-7 gene, resulting in the production of a toxic polyglutamine- expanded ataxin-7 protein. As it is the expression of the toxic gene product that drives all subsequent disease pathology in SCA7 and in related polyglutamine and neurodegenerative disorders, an accepted therapeutic paradigm for treating these diseases is to terminate the expression of the mutant gene product;hence, we will pursue ataxin-7 knock-down therapy using an antisense oligonucleotide (ASO) approach by continuing ongoing studies, being performed in collaboration with ISIS Pharmaceuticals. In this project, we will evaluate both human ataxin-7 ASOs and mouse ataxin-7 ASOs in SCA7 transgenic mice and SCA7 knock-in mice respectively, as these complementary approaches will allow us to compare the results of allele-specific gene knock-down (SCA7 transgenic mice) with non-allele-specific gene knock- down (SCA7 knock-in mice) in an in vivo setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS082112-02
Application #
8551817
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gwinn, Katrina
Project Start
2012-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$186,969
Indirect Cost
$66,344
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ramachandran, Pavitra S; Boudreau, Ryan L; Schaefer, Kellie A et al. (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22:1635-42
Ramachandran, Pavitra S; Bhattarai, Sajag; Singh, Pratibha et al. (2014) RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. PLoS One 9:e95362