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MDA’S SEARCH FOR TREATMENTS AND CURES

	Three of the MDA scientists in the forefront of FA research are Grazia Isaya at the Mayo Clinic in Rochester, Minn. (top left); Kenneth Fischbeck at the National Institute of Neurologic Disorders and Stroke in Bethesda, Md. (lower left); and Massimo Pandolfo at the Université Libre de Bruxelles in Brussels, Belgium (above).

In 1988 MDA-funded scientists linked Friedreich’s ataxia to chromosome 9, and in 1996 they identified FA-causing mutations in the frataxin gene. By the next year, they’d devised a genetic test for FA.

Besides this important advance in diagnosis and carrier testing, the discovery of frataxin mutations has opened doors to several potential treatments for FA.

The frataxin gene was unknown until it was tagged as the culprit behind FA. Since then, much research has focused on determining the normal functions of the frataxin protein in an effort to find ways of compensating for its shortage in FA.

An important breakthrough came when MDA-funded scientists discovered that a single-celled organism, baker’s yeast, has its own version of frataxin. Baker’s yeast has a long history in genetic research, and when the scientists eliminated the frataxin gene in yeast cells, they found that the cells’ mitochondria accumulated iron and were damaged by oxidative stress. Cells from people with FA proved to have similar defects.

These studies laid the groundwork for testing antioxidants — like idebenone, coQ10 and vitamin E — first in laboratory experiments on frataxin-deficient cells, and then in clinical trials involving people with FA.

Given that iron buildup occurs in FA, MDA-funded scientists are also investigating the possibility of treating FA with iron chelators — drugs that capture iron and carry it through the body to be excreted.

Meanwhile, MDA-funded research is leading to more efficient tests of these potential treatments. In 2001, scientists reported that they’d developed a mouse model of FA that can be used to determine which treatments should be fast-tracked into clinical trials. And researchers are developing better ways to monitor oxidative stress, as well as heart and muscle function in people with FA, which will make it easier to interpret clinical trial results.

While MDA-funded scientists are hopeful that antioxidants and iron chelators will slow the course of FA, they’re also striving to achieve long-term correction of FA using gene therapy. In a step toward that goal, they’ve found that the expanded repeats underlying FA cause frataxin DNA to fold into an abnormal shape that inhibits production of the frataxin protein. Although it will be many years before gene therapy can be tested in humans, laboratory experiments have shown that it’s possible to design short fragments of DNA that prevent abnormal folding of frataxin DNA and increase its conversion into frataxin protein.

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