Exciting Research Directions

In February 2003, the Friedreich's Ataxia Research Association (FARA) and the National Institutes of Health (NIH) co-hosted the second international Friedreich's ataxia (FA or FRDA) in Bethesda, Maryland. About 100 scientists from 12 different countries came together to compare findings, share insights and chart the course ahead in the search for treatments and a cure for FA.

Since the gene discovery in 1996, scientists have identified the protein that should be expressed by the faulty FA gene. Christened frataxin, after the disorder, it performs its function at the walls of the mitochondria (the energy factories of our cells).

Scientists are closing in on the structure of the protein, its function, and the mechanism of the gene's failure. Clinical trials of anti-oxidants are underway, and additional trials exploiting new knowledge are on the horizon.

There appear to be two basic mechanisms that cause problems with the FA gene.

• Large numbers of repeats of three nucleotides (the building blocks of DNA) on defective chromosomes cause the gene to fold back onto itself. This forms a triplex (or "sticky DNA") on the gene structure so that the gene's code is often not effectively read, and much less of the protein is produced.
• In a small number of cases, the disorder can also be caused by a point mutation, in which one nucleotide is replaced by another, or an extra one is inserted or deleted. These "misspellings" also mean that the protein is not formed correctly, and so does not function correctly..

In people diagnosed with Friedreich's ataxia, the shortage of the frataxin protein results in excessive free radicals that damage and kill cells, and excessive iron accumulations in the mitochondria. As a result, the mitochondria produce far less energy than normal and the cell eventually dies. Research is now identifying the mechanism behind these effects.

Collaborative, multinational, multi-center clinical trials for Friedreich's ataxia are being planned. These trials now involve the use of antioxidants to slow the production and prevent the effects of free radicals. As research proceeds to identify further the underlying mechanism of the disease, other approaches to treatment will emerge.

Ten years ago, a diagnosis of Friedreich's ataxia brought patients and parents to a stark reality--"there is no treatment, and there is no cure." Now, things are changing, and changing rapidly.

Within the scientific community, Friedreich's ataxia has become "a hot field" that is drawing more and more scientists into this research. Recent discoveries have opened new and exciting avenues for both fundamental understanding of the disorder and clinical trials leading to new treatments. With an increase in funding, which is the purpose of this site, the pace of research will increase, and a cure can be found. Alone, we cannot succeed. But together, there is nothing we cannot accomplish.

Research directions as of August, 2004
For details, see the FARA and MDA sites.

Lipid-soluble antioxidants for FA
Find a way to reduce free-radical damage that destroys cells. The following compounds/foods have possibilities.

• Idebenone
• Mitoquinone
• Coenzyme Q10 (CoQ10) with Vitamin E
• Selenium, Alpha Lipoic Acid, N-Acetyl-L-Cysteine (NAC), green tea, and blueberries

Develop Ataxia Scales (Clinical Measures)
Figure out how to objectively measure whether treatment is successful so studies and therapies can be compared.

Gene-Based Approaches

• Use molecular surgery to remove the excess nucleotide repeats
• Attach additional pieces of DNA that would interrupt or stabilize the excessive repetition of nucleotides
• Introduce a small amount of DNA that would serve to bypass or “patch over” the genetic defect
• Replace the entire defective gene by an unaffected gene

Delivery vehicle (vector)
Find a vehicle that will take gene-based therapies to the right place in the cells

Frataxin Protein-Based Approaches
Synthesize proteins and deliver them to mitochondria

Mouse Models
Create genetically modified families of mice to study the disease process and test therapeutic approaches

• Knock-Out (disable genes)
• Knock-In (put genes in)
• Combo of Knock-out and Knock-In

Iron Chelation
Remove excess iron from the mitochondria