Drug Insight: antioxidant therapy in inherited ataxias

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.