Expert Opin Investig Drugs. 2003 Feb;12(2):235-45.

Friedreich's ataxia: iron chelators that target the mitochondrion as a therapeutic strategy?

Richardson DR.

Children's Cancer Institute Australia for Medical Research, Iron Metabolism and Chelation Program, High St (PO Box 81), Randwick, Sydney, New South Wales, 2031, Australia.

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.

This is of course an interesting question. Could an iron chelator have a place in the treatment of FA?

However, before this question can be answered, it is necessary to know the extent to which iron accumulation contributes to the pathophysiology of FA. In the final analysis this comes down to our understanding of the role of frataxin. In this context, a number of studies support a role of frataxin in iron-sulphur cluster biosynthesis and that detectable iron accumulation appears to be a late event in the disease process. It should thus be appreciated that antioxidants and iron chelators may at best reduce the damage caused by free radicals, but could not be expected to overcome the damage caused directly by deficits in all the enzymes that depend on iron-sulphur clusters. Nontheless, it is possible that failure to use iron properly for iron-sulphur biosynthesis in patient cells may lead to an increase in labile iron (this remains to be demonstrated experimentally), thus contributing to increased generation of free radicals and oxidative, damage. In such a case, an iron chelator that can remove labile iron from within cells and preferably also from the mitochondria could potentially enhance any therapeutic benefit from anti-oxidants.

So what iron chelators are available for patient treatment?

1) Desferal or desferrioxamine (manufactured by Novartis) is being used for the treatment of thalassaemia patients. It cannot go across cell membranes and binds iron very strongly. It would not be suitable for the treatment of FA patients who do not have overall iron overload.

2) ICL670: This is a new chelator that is being developed by Novartis to replace desferal, since it can be taken orally. It is currently undergoing trials for thalassaemia and other iron overload conditions, but I am not aware of any effort to test it in FA. Although it seems better than desferal in its oral bioavailability, it is not clear whether this chelator can bind labile iron within cells and then bring it out. However, it may contribute to a net outward movement of iron indirectly, although this could be more difficult to envisage for the brain. Its toxicity profile in patients without overall iron overload remains to be established. Its low rate of excretion and metabolism could enable its use in low doses for patients without general iron overload, thus avoiding overall iron excetion.

3) Deferiprone or L1: This is a lipid soluble iron chelator that can go across membranes both as a free compound and with iron bound to it. As such it can also cross the blood-brain barrier. It is known to bind labile iron within cells and to reduce oxidative damage, but I am not aware of any definite evidence that it can bind and remove iron from mitochondria. L1 does not bind iron very strongly, so it could release iron to other molecules when iron concentration is not high. Thus L1 could potentially be used to cause redistribution of iron from mitochondria to the cytoplasm and plasma, without overall iron excretion. However, L1 is rapidly metabolised after oral administration and there is no information on possible effective doses or toxicity in patients without overall iron overload.

The use of L1 in thalassaemia has been marked by a lot of controversy due to the early claims by Nancy Olivieri that L1 caused liver fibrosis. However, several large studies have failed to substantiate such claims, while there is significant evidence for a beneficial role of L1 in cardiomyopathy in thalassaemia patients.

In conclusion, among the three iron chelators which are in or close to the market, L1 currently looks as the most interesting for Friedreich ataxia, while ICL670 may be worth looking at, as it moves closer to the market for thalassaemia and other diseases of systemic iron overload. However, this is not to say that any patient should be rushing to test any iron chelators on themselves. Cellular and animal studies are necessary to examine a possible role of iron chelators in FA, while safety studies in normal subjects may benecessary before it may be possible to determine whether an iron chelator could have a beneficial role in FA.

Thank you,



Head, Cell & Gene Therapy (CAGT) Research Group
The Murdoch Childrens Research Institute, Royal Children's Hospital
Flemington Road, Parkville 3052, Melbourne, Australia
Tel: (61 3) 8341 6232; Fax: (61 3) 9348 1391; Mobile: 0402 385 440

Associate Professor, Dept of Paediatrics, University of Melbourne

Honorary Senior Scientist, The Cyprus Institute of Neurology & Genetics