Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. SCA7 patients develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation or modify the processing of targeted RNAs. Here we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models via injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded significant improvements in treated SCA7 mice. In SCA7 mice with significant retinal disease, intravitreal injection of Ataxin-7 ASO also improved visual function despite initiating treatment after symptom onset. By using color fundus photography and autofluoresence imaging, we also determined the nature of retinal degeneration in human SCA7 patients; we observed variable disease severity, and catalogued rapidly progressive degeneration. Given the accessibility of neural retina, availability of objective, quantitative read-outs for monitoring therapeutic response, and rapid disease progression, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

One sentence Summary:

Intravitreal injection of antisense oligonucleotides improves visual function in SCA7 mice that model retinal degeneration phenotypes in human patients.