RNA Interference Applications for Machado-Joseph Disease

Abstract

Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3), is a dominantly inherited neurodegenerative disease caused by abnormal CAG expansions in MJD1 gene, which translate to an overexpanded tract of glutamines in the ataxin-3 (ATXN3) protein. Since the identification of the causative gene, a huge effort was made toward the development of animal models for MJD/SCA3, to increase the understanding of the molecular mechanisms underpinning disease pathogenesis, and to develop therapeutic strategies for the disease. Nevertheless, until now there are no therapies available capable of stopping or delaying the disease progression, which culminates with the death of the patients. Therefore, there is an urgent unmet need for therapeutic solutions, for which gene therapy stands out. The RNA interference (RNAi) mechanism discovery allowed the identification of small RNA molecules with the ability to regulate gene expression. For gene therapy, RNAi provided a way to silence mutant genes, which are particularly useful in dominantly inherited diseases. In the last years, several studies have focused on using RNAi molecules to target mutant ATXN3. The results showed that this could be an efficient and safe strategy for modifying MJD/SCA3 progression. Now, an additional effort must be done to translate these results into clinical trials.