Spinocerebellar ataxia (SCA) is a neurodegenerative disease characterized by progressive impairment of motor function with neuronal cell loss in the cerebellum. Over 40 causative genes have been identified in SCAs so far; however, no disease-modifying therapy is currently available. However, the research group from the University of Tokyo and the University of Chicago has developed a novel gene therapy for spinocerebellar ataxia type 6 (SCA6). SCA6 is a neurodegenerative disease affecting motor function in the patients. The researchers used a disease-specific microRNA (miRNA), a small RNA, to selectively inhibit the production of a disease-associated protein.

SCA6, the second-most common type of dominantly inherited SCAs in Japan, is caused by expanded repeat sequences in the CACNA1A gene. Although the CACNA1A gene has been thought to encode the calcium channel (αA1) necessary for neuronal cell activity, in 2013 a research group at the University of Chicago reported that, in addition to αA1, the CACNA1A gene also codes a second protein (α1ACT), a transcription factor, responsible for regulating gene expression, and that mutant α1ACT rather than αA1 causes neurodegeneration in SCA6.

Professor Shin-ichi Muramatsu from the Center for Gene and Cell Therapy, Institute of Medical Science, the University of Tokyo, and his collaborators have developed a novel therapeutic approach for SCA6 by selectively blocking α1ACT expression. They identified a miRNA that selectively inhibits the translation of α1ACT from CACNA1A messenger RNA.

They used an improved adeno-associated virus (AAV) vector to efficiently deliver a disease-specific miRNA into the neuronal cells in SCA6 model mice. They also showed that an AAV vector-mediated miRNA delivery protected mice from the motor impairment and neuronal cell death in the cerebellum. Prof Muramatsu explained that a series of reports have recently suggested that miRNAs may hold therapeutic promise for treating cancer, metabolic diseases, and inflammation.

Scientists have previously demonstrated that an AAV vector-mediated miRNA delivery is effective in a mouse model of spinal and bulbar muscular atrophy, another type of neurodegenerative disease. Researchers are able to use their AAV vector systems to have a widespread transduction of genes throughout the brain and spinal cord in monkeys and pigs by an intrathecal administration. They would like to apply their strategy to the patients with SCA6 in clinics in the near future.