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Spinocerebellar ataxias: prospects and challenges for therapy development

Nature Reviews Neurology volume 14, pages 590–605 (2018)Cite this article

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An Author Correction to this article was published on 08 November 2018

This article has been updated

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.

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Fig. 1: Hereditary degenerative ataxias caused by expanded microsatellite repeats.
Fig. 2: Diagnostic algorithm for progressive ataxias.
Fig. 3: Therapeutic strategies for the SCAs.
Fig. 4: Sample size estimation for evaluation of drug efficacy in SCA1.
Fig. 5: Transatlantic SCA consortia.
Fig. 6: Biomarkers for SCAs.

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Change history

  • 08 November 2018

    In Table 3 of this article as originally published, a sentence within the column “Comments” in the row “SCA6” contains an error. The text incorrectly reads “Needs rigorous preclinical studies in SCA3 animal models”. This sentence has been corrected to “Needs rigorous preclinical studies in SCA6 animal models” in the PDF and HTML versions of the article.

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Acknowledgements

This work was supported by a grant from the US NIH (U01 NS104326-01) to T.A. (contact principal investigator), G.Ö. (multiple principal investigator) and H.L.P. (multiple principal investigator). T.A. is funded by the NIH (R01 NS083564), the National Ataxia Foundation and the Harriet and Joe B. Foster Endowment Fund on spinocerebellar ataxia (SCA) research and is collaborating with Pacific Biosciences on single-molecule real-time sequencing of the expanded SCA10 tandem repeat. G.Ö. receives grant funding from the NIH (R01 NS080816), the National Ataxia Foundation and Takeda Pharmaceuticals on SCA research. The Center for Magnetic Resonance Research is supported by the US National Institute of Biomedical Imaging and Bioengineering grant P41 EB015894 and the US Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. H.L.P.’s work on SCAs is funded by the NIH (R01 NS038712), the National Ataxia Foundation, the Alfred Taubman Medical Research Institute, the University of Michigan Center for the Discovery of New Medicines, Cydan and the SCA Network of Sweden. He collaborates with Ionis Pharmaceuticals on antisense oligonucleotide therapy development for SCA3. The authors thank C. Potvin for helping with manuscript preparation and L. Eberly for assistance with sample size calculations.

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  1. Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA

    Tetsuo Ashizawa

  2. Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, USA

    Gülin Öz

  3. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Henry L. Paulson

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All authors researched data for the article, made substantial contributions to discussion of content, wrote the article and reviewed and/or edited the article before submission.

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Correspondence to Tetsuo Ashizawa.

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T.A. has received honoraria and travel support from Pacific Biosciences. G.Ö. has received funding from Takeda Pharmaceuticals for a spinocerebellar ataxia (SCA) preclinical trial. H.L.P. recently completed a research contract with Ionis Pharmaceuticals for ASO treatments of SCA3.

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Ashizawa, T., Öz, G. & Paulson, H.L. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol 14, 590–605 (2018). https://doi.org/10.1038/s41582-018-0051-6

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