Friedreich's ataxia (FA) is a severe inherited
spinocerebellar ataxia that primarily affects the nervous system and heart leading to early confinement in a wheelchair and death. The gene defective in FA, FRDA, encodes a
mitochondrial protein known as
frataxin. A triplet repeat expansion within intron 1 of the FRDA gene results in a marked decrease in
frataxin expression. Over the last 5 years it has become clear that this results in mitochondrial
iron accumulation that generates oxidative stress and results in damage to critical
biological molecules. Drugs that reduce oxidative stress have a limited effect on the progression and pathology of the disease, probably because these agents cannot remove the
iron accumulation. In this review, the potential of
iron chelators, namely the 2-pyridylcarboxaldehyde isonicotinoyl
hydrazone (PCIH) analogues, as agents to remove mitochondrial
iron deposits is discussed. These
ligands have been specifically designed to enter and target mitochondrial
iron pools, which is a property lacking in
desferrioxamine, the only
chelator in widespread clinical use. This latter
drug may not have any beneficial effect in FA patients, probably because of its hydrophilicity that prevents mitochondrial access. Indeed, standard chelation regimens will probably not work in FA, as these patients do not exhibit gross
iron-loading. Considering that there is no effective treatment for FA, it is essential that the therapeutic potential of
iron chelators that target mitochondrial
iron pools is assessed experimentally.