Iron in the heart for Friedreich's

Novel drugs that target iron accumulation could prove a potential therapy for the cardiomyopathy common to Friedreich's ataxia, a rare autosomal genetic disorder.

Friedreich's ataxia is the result of a mutation in the FXN gene, which codes for a novel protein called frataxin. Frataxin is exported to the mitochondria and removes iron concentrations in the cytoplasm.

A toxic build-up of iron is thought to be the cause of the destruction of neurons seen in Friedreich's ataxia, leading to sensory impairments and loss of co-ordination. It is also thought to be behind the heart disease that is a frequent cause of death in Friedreich's patients.

In a new study by Australian and Canadian researchers, published in the July 15 issue of the US Proceedings of the National Academy of Sciences, a mouse model of Friedreich's ataxia was used to show that frataxin deficiency alters cardiac iron metabolism by changing the way iron is trafficked.

The team, led by Professor Des Richardson and PhD student Megan Whitnall of the University of Sydney, found that increased iron loading in the myocardium was due to the marked uptake of transferrin, a protein which binds to iron and delivers it into the cell.

Iron chelation agents are a target for several groups around the world, with some in Phase III trials. The Australian researchers looked at a combination of desferrixamine (DFO), which has been shown to have some ability in rescuing fibroblasts from oxidant stress but which is unable to permeate the mitochondrion, and a membrane-permeable chelator called pyricoxal isonicotinoyl hydrazone (PIH), which mobilises mitrochondrial iron.

They found that combining the two prevented cardiac iron loading and limited cardiac hypertrophy in the mouse model, suggesting it should be further explored as a potential therapy.