Several neurodegenerative diseases arise from a mechanism known as trinucleotide repeat expansion and none are more common than the polyglutamine disorders. These disorders are caused by an expansion in a polymorphic CAG repeat beyond the normal size range for that given gene. The phenotype and age of onset of these diseases is highly dependent on the length of the expansion and the nature of the gene. 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).

We are developing antisense oligonucleotides (AOs) as genetic therapeutic agents to treat a number of inherited diseases. Recently, the FDA granted accelerated approval for a phosphorodiamidate morpholino oligomer (PMO), Exondys 51, developed in this laboratory as a treatment for Duchenne muscular dystrophy.  Exondys 51 has been in clinical trials for nearly 5 years and has been shown to delay muscle wasting and disease progression. PMOs can be very efficient in changing pre-mRNA processing, are metabolically inert and have an excellent safety profile to date. This study aims to extend AO-induced splice switching to other conditions, in particular using AO-mediated exon skipping to develop a potential therapeutic strategy for the treatment of SCA3. Preliminary in vitro data show that it is possible to skip the CAG expanded repeat contained in ATXN3 exon 10 and still maintain many normal functions. Surprisingly, several animal knock-out models of ATXN3 show no increased morbidity, and hence 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. If successful, these methods will be tested using PMOs in patient cells as well as in vivo mouse models.