Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

Adult human neurodegenerative diseases have no disease-modifying treatments. We used spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease1, as a model to test RNA-targeted therapies(2) in two SCA2 mouse models. Both models recreate progressive adult-onset dysfunction and degeneration of a neuronal network including decreased firing frequency of cerebellar Purkinje cells (PCs) and decline in motor function(3,4). We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). Here we show that the most promising lead, ASO7, downregulated ATXN2 mRNA and protein resulting in delayed onset of SCA2 phenotypes. After delivery by intracerebroventricular injection (ICV) to ATXN2-Q127 mice, ASO7 localized to PCs, reduced cerebellar ATXN2 expression below 75% for >10 weeks without microglial activation, and reduced cerebellar ataxin-2 protein. ASO7 treatment of symptomatic mice improved motor functioning compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related PC proteins including Rgs8, Pcp2, Pcp4, Homer3, Cep76, and Fam107b. Most surprisingly, firing frequency of PCs returned to normal even when treatment was initiated >12 weeks after motor phenotype onset in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.