Perspectives for Treatment

All FA patients carry at least one allele with an expanded d(GAA) repeat and therefore make an insufficient amount of otherwise normal frataxin. If it were possible to increase their frataxin production to levels that are similar to those of healthy carriers, one could possibly stop the course of the disease and maybe even induce some improvement. Increased frataxin production could be obtained:

1. Through gene replacement therapy, i.e., by introducing a frataxin gene without the d(GAA) expansion into the patient cells.

2. By giving frataxin directly. The protein should, however, be modified such that it will be able to reach the nerve cells affected by the disease and the mitochondria within these cells.

3. By using molecules that can destabilize the triple-helical structure formed by the d(GAA) repeat and shift the equilibrium toward the physiological double helix that allows frataxin expression.

Though still in their infancy, all these approaches are under study. Recently, encouraging results have been obtained for gene replacement therapy, with partial correction of the oxidative stress hypersensitivity of FA fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors (Fleming et al. 2005).

Additional ways to treat the disease may become apparent from studies on the function of frataxin. On the basis of these findings, therapeutic approaches aimed at controlling the levels of free radicals and regulating respiratory chain activation may be proposed. Concerning antioxidant molecules and respiratory chain stimulants, some coenzyme Q derivatives (idebenone, CoQ-10) have already yielded promising results, not only in experimental models (Seznec et al. 2004), but also in clinical trials, at least with respect to FA cardiomyopathy (Buyse et al. 2003; Mariotti et al. 2003). Automated high-throughput tests to evaluate a large number of molecules for their ability to correct the functional consequences of frataxin deficiency are under way. An intriguing possibility would be the identification of small molecules capable of effectively replacing frataxin by binding mitochondrial iron and increasing its bioavailability.

Last, cellular therapies, in particular the use of stem cells, could be useful in the treatment of FA. However, the widespread nature of neurodegeneration in FA is a major obstacle to this approach since it would require the widespread delivery of cells in the central nervous system of the patients.

Remarkable progress has been made in understanding the pathogenesis of FA since the gene responsible was discovered in 1996. In addition, investigating the pathogenesis of FA has stimulated research on numerous basic areas of biology, from DNA structure and biochemistry to iron metabolism. However, most excitingly perhaps is the now realistic perspective of developing a treatment for this so far incurable neurodegenerative disease.

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