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

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Science Translational Medicine  31 Oct 2018:
Vol. 10, Issue 465, eaap8677
DOI: 10.1126/scitranslmed.aap8677

Improving vision in spinocerebellar ataxia

Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder caused by mutations in the ATAXIN-7 gene. SCA7 is characterized by impairments in coordination, balance, and speech and by retinal degeneration that results in complete blindness. Here, Niu et al. developed a strategy for treating visual impairments in SCA7 by inhibiting the mutated Ataxin-7 in the retina using antisense oligonucleotides (ASOs). Intravitreal injection of ASOs specifically targeting the mutated Ataxin-7 reduced protein expression in the retina and ameliorated pathology and vision loss in a SCA7 mouse model. The results suggest that ASOs targeting ATAXIN-7 might be effective in treating retinal degeneration in patients with SCA7.


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. Patients with SCA7 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 of the disease after 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 improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

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