RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration.

Pavitra S Ramachandran,Albert R Laspada,Ryan L Boudreau,Stewart Thompson,Sajag Bhattarai,Arlene V Drack,Pratibha Singh,Beverly L Davidson,Tiansen Li

doi:10.1371/journal.pone.0095362

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease characterized by loss of motor coordination and retinal degeneration with no current therapies in the clinic. The causative mutation is an expanded CAG repeat in the ataxin-7 gene whose mutant protein product causes cerebellar and brainstem degeneration and retinal cone-rod dystrophy. Here, we reduced the expression of both mutant and wildtype ataxin-7 in the SCA7 mouse retina by RNA interference and evaluated retinal function 23 weeks post injection. We observed a preservation of normal retinal function and no adverse toxicity with ≥50% reduction of mutant and wildtype ataxin-7 alleles. These studies address an important safety concern regarding non-allele specific silencing of ataxin-7 for SCA7 retinal therapy.

Highlights

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by ataxia, which manifests as loss of motor coordination, dysarthria, slower reflexes, and retinal degeneration leading to vision loss
SCA7 is caused by the expansion of CAG repeats in the ataxin7 gene (ATXN7), which translates into a polyglutamine expanded protein
To target the photoreceptor cells in SCA7 mice, AAV2/1.miS4 was subretinally injected into one eye and the contra-lateral eye was subretinally injected with AAV2/1.miC

Summary

Introduction

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by ataxia, which manifests as loss of motor coordination, dysarthria, slower reflexes, and retinal degeneration leading to vision loss. Anticipation is a key feature of this disease and for SCA7 patients with early onset disease, vision loss can occur early in life, followed by ataxia [1]. SCA7 is caused by the expansion of CAG repeats in the ataxin gene (ATXN7), which translates into a polyglutamine expanded protein. Studies in SCA7 mouse models and in vitro studies have demonstrated that polyglutamine expanded ataxin-7 disrupts the transcription of CRX, the cone-rod homeobox protein, in turn affecting the transcription of CRX-regulated genes resulting in a cone-rod dystrophy [4,5]

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