Spinocerebellar ataxias: prospects and challenges for therapy development (2018)

By Tetsuo Ashizawa et al. in Nature Reviews Neurology 2018

Abstract: The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.

Key points:

Spinocerebellar ataxias (SCAs) are a group of dominantly inherited degenerative disorders that principally involve the cerebellum and its connections.

Insights into the pathogenic mechanisms of many SCAs have suggested promising routes to symptomatic and disease-modifying therapy.

Clinical research consortia for SCAs have started international collaborations to share and analyse natural history data.

The Scale for Assessment and Rating of Ataxia is the best validated clinical outcome assessment measure, but additional measures should be developed with improved responsiveness to changes that are directly relevant to patients’ lives.

MRI and magnetic resonance spectroscopy have emerged as potentially powerful biomarkers for disease activities and progression, but target engagement biomarkers, especially molecular biomarkers in biofluids, are yet to be developed.

Collective efforts in SCA clinical research within the past few years have improved the prospects for eventual successful therapeutic development for the SCAs.