Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disease, which 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 ATXN3. This study aims to use antisense oligonucleotide (AO) mediated exon skipping to develop a therapeutic strategy for the treatment of SCA3.
Initial in vitro data using 2’-O-methyl AOs in patient cells show that it is possible to create an internally truncated protein, missing the toxic CAG repeat contained in ATXN3 and still maintain normal function of the protein. Confirmatory data using the clinically relevant phosphorodiamidate morpholino oligomer (PMO) chemistry showed complementary positive results to 2’O-methyl data. Additionally, significant downregulation of both the mutant and wild-type protein was observed, allowing for a combination of benefits. However, PMO is widely considered to be a superior chemistry when compared to 2’-O-methyl, as they are chemically stable and have an excellent safety profile to date. Further data shows that PMO chemistry is longer lasting and significantly better tolerated by cells. Therefore, this study provides a possible therapeutic strategy to treat SCA3.