The use of antisense oligonucleotide-mediated exon skipping to treat spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is one of nine polyglutamine disorders. Although SCA3 is pathogenically heterogeneous, the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected individual. There is currently no cure, nor effective treatment strategy for affected individuals. SCA3 is caused by an expanded polyglutamine tract found in ataxin‐3, resulting in conformational changes that lead to toxic gain of function. This expanded glutamine tract is located at the 5' end of the penultimate exon (exon 10) of the ATXN3 gene (14q32.1). This study aims to use antisense oligonucleotide (AO) mediated exon skipping to develop a potential therapeutic strategy for the treatment of SCA3. Preliminary in vitro data in healthy cells show that it is possible to create a novel, internally truncated protein, missing the CAG repeat contained in ATXN3 and still maintain many normal functions. Ongoing research is to be conducted in patient cells to determine whether the CAG expansion will affect the efficacy of the AOs to product a truncated protein. This research shows proof of concept that the removal of exon 10 alone, although out of frame, is possible. Alongside this, another strategy may be to disrupt normal ATXN3 expression by targeting exons which disrupt the reading frame and thereby down‐regulate protein expression. We hypothesize that reducing the normal and mutant protein may alleviate symptoms and/or delay onset or slow progression of the disease.