degeneration of nerve fibres observed in the mouse model of X-linked adrenoleukodystrophy (X-ALD), the most frequently inherited leukodystrophy, so we looked at mitochondria for further clues. We found that the X-ALD mice showed a loss of mitochondria at 12 months of age, prior to disease symptoms, so this could not be a consequence of the disease, but rather a contributing factor. We also knew that the pathway involved in the mitochondrial loss could be treated by the use of the diabetes drug pioglitazone, so we decided to test its effect in the mice", Professor Pujol will say.
Pioglitazone halted the nerve fibre degeneration by preventing the loss of mitochondria, and inhibiting metabolic failure and oxidative stress in the treated mice, and hence also halted locomotor disabilities. The researchers were able to prove this both through analysis of spinal cords post mortem, and in vivo by putting the mice through a number of physical tests.
Although X-ALD is a relatively rare disease with a minimum incidence of 1 in 17 000 males, there are other neurodegenerative disorders caused by myelin sheath degeneration, for example multiple sclerosis, and many others where impaired bioenergetics combined with oxidative stress and degeneration of axons are known to be involved. The latter category of disease includes Parkinson's, Huntington's, and Alzheimer's. "It is possible that our findings may be relevant to these conditions as well," says Professor Pujol.
"Following on from these promising results, together with Professor Patrick Aubourg from the Hôpital Bicêtre, Paris, we will shortly be starting a multi-centre phase II clinical trial of pioglitazone in adult patients suffering from a late onset variant of adrenoleukodystrophy. Our research has shown that it will be feasible to monitor the biological effects of the drug by looking for biomarkers of oxidative damage in blood cells or plasma. We are happy to have made a contribution to finding a simple and effective treatment to a group of devastating diseases", she will conclude.