Drug Insight: Antioxidant Therapy in Inherited Ataxias

Massimo Pandolfo


Nat Clin Pract Neurol. 2008;4(2):86-96. 

In This Article

Summary and Introduction


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.


The concept that oxidative damage contributes to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and the inherited ataxias, has prompted attempts to treat these conditions with various antioxidants. The results have been largely negative or inconclusive, partly because the choice of the drug to be tested and the determination of its dosage were often based on an incomplete knowledge of the relevant pathogenic mechanisms and pharmacological properties of the investigated molecule. Another confounding factor has been the poor design of trials, many of which have been uncontrolled and underpowered, with no clearly defined end point. This situation is changing, however, owing to progress in basic and clinical research and the convergence of these approaches in a translational research arena.

The brain detects and overcomes oxidative stress through a complex network of 'longevity assurance processes' integrated with the expression of genes termed 'vitagenes'. These vitagenes include genes encoding heat-shock proteins, which facilitate correct protein folding, and the gene encoding heme oxygenase-1, an inducible and redox-regulated enzyme that promotes cellular antioxidant defense.[1] Treatments that can activate this response are likely to be neuroprotective in a range of conditions. Various compounds are thought to have this property; for example, acetyl-L-carnitine induces heme oxygenase-1, in addition to heat-shock protein 70 and the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2, or SODM).[2]

In addition to understanding the general response to oxidative stress, it is now becoming possible to dissect the pathogenic mechanisms of different neurodegenerative diseases, the role that oxidative stress has in each case, and the specific pathways that are activated, thereby enabling disease-specific targets for antioxidant treatments to be identified. Knowledge of the basic and clinical pharmacological properties of antioxidant drugs is increasing, and, importantly, the design of clinical trials has improved substantially in recent years. Several advances, including the development and validation of rating scales and other tools (including biomarkers) to assess disease progression, functional capacity and quality of life, better characterization of the clinical features and natural history of neurodegenerative diseases, and the establishment of international consortia of investigators, are paving the way for appropriately designed, controlled and adequately powered studies, even for rare disorders. These efforts have been especially productive in the field of inherited ataxias, in particular Friedreich ataxia (FRDA). FRDA represents a prototypical disease in which oxidative damage directly derives from the primary molecular defect and lies at the core of the pathogenesis. This Review will focus first on the rationale for antioxidant treatment and on the results of clinical trials in FRDA, and then on the possible use of antioxidants for other inherited ataxias.


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