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Drug Insight: antioxidant therapy in inherited ataxias

Nature Clinical Practice Neurology volume 4, pages 86–96 (2008)Cite this article

Abstract

The inherited ataxias are a large, heterogeneous group of neurodegenerative disorders caused by a variety of gene mutations, the effects of which are exerted through different pathogenic mechanisms. Despite this diversity, oxidative stress seems to be a common factor in the pathogenesis of these disorders, indicating that antioxidants might be potential therapeutics for these currently incurable conditions. Some inherited ataxias, such as ataxia with vitamin E deficiency, are directly caused by defects in small-molecule antioxidants and might be treated by supplying the defective molecule. In most ataxias, however, oxidative stress has more-complex disease-specific causes and consequences, which must be better understood to enable effective treatments to be developed. Results from studies in cellular and animal models need to be brought to the clinic through rigorous trials. The rarity of each of these diseases can, however, make trial design and execution a very difficult task. Challenges include the development of validated clinical assessment tools and biomarkers, and the recruitment of a sufficient number of patients. Despite these obstacles, marked progress has been made in the case of Friedreich ataxia, a disease that has oxidative stress at the core of its pathogenesis. This condition seems to respond to idebenone, a coenzyme Q analog that has antioxidant and oxidative-phosphorylation-stimulating properties.

Key Points

  • Oxidative stress is a key factor in the pathogenesis of inherited ataxias, but the mechanisms involved vary between different conditions, necessitating distinct therapeutic approaches

  • Friedreich ataxia (FRDA) is caused by deficiency of a mitochondrial protein, frataxin, which has direct antioxidant and iron-regulatory functions, making this disease a prime candidate for antioxidant therapy

  • Clinical rating scales and biomarkers for FRDA are rapidly being developed and are beginning to be used in controlled, double-blind clinical trials

  • Several antioxidants have been tested in FRDA, but placebo-controlled, double-blind trials have only been conducted with idebenone; a recent phase II trial provided very encouraging results regarding the safety and possible efficacy of this drug

  • A few rare forms of ataxia are directly attributable to the deficiency of small-molecule antioxidants—such as vitamin E and coenzyme Q10—for which replacement therapy is possible

  • There is a rationale for testing antioxidants in ataxias attributable to DNA repair defects, autosomal-dominant spinocerebellar ataxias and ataxias with primary mitochondrial dysfunction, but no controlled clinical trials have been conducted to date

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Figure 1: Frataxin function and oxidative stress in Friedreich ataxia.

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Acknowledgements

Support to the author for research in inherited ataxias comes from the GoFAR foundation (Italy), the CRT foundation (Italy), the Friedreich Ataxia Research Alliance (USA), Ataxia UK, Ataxia Ireland, the Belgian Ministry of Scientific Policy (Interuniversity Attraction Poles 6), the Belgian National Scientific Research Funds (FNRS) and the European Community (Framework 6 integrated project EUROSCA).

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  1. Service de Neurologie, Université Libre de Bruxelles-Hôpital Erasme, Route de Lennik 808, B-1070 Bruxelles, Belgium massimo.pandolfo@ulb.ac.be

Authors and Affiliations

  1. M Pandolfo is Chief of the Department of Neurology at the major teaching hospital of the Free University of Brussels, Brussels, Belgium.,

    Massimo Pandolfo

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Competing interests

M Pandolfo has acted as a consultant for ApoPharma and Santhera, and is a patent holder with Athena Diagnostics.

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Pandolfo, M. Drug Insight: antioxidant therapy in inherited ataxias. Nat Rev Neurol 4, 86–96 (2008). https://doi.org/10.1038/ncpneuro0704

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