Friedreich's Ataxia (FRDA)

Research

Expanded frataxin genes

In the 1990s, the identification of mutations in the frataxin gene (from which frataxin protein is produced) as the underlying cause of Friedreich's ataxia (FRDA) opened the door to a much better understanding of FRDA and new avenues for treatment development. MDA funding led to the discovery of the frataxin gene.

Although two types of FRDA-causing mutations exist, by far the most common is a GAA trinucleotide repeat expansion — a region of DNA containing greater-than-normal numbers of the chemical phrase "GAA."

Five to 30 GAA repeats are within normal range, but in people with FRDA the GAA repeats number is in the hundreds, with the larger repeat expansions generally correlating with earlier onset and greater disease severity.

Approximately 96 percent of people with FRDA have two GAA repeat expansions, one on each chromosome. The other roughly 4 percent possess two different mutations: an expansion on one chromosome and a conventional gene mutation (most of which are truncations, or deletions) on the other.

Importantly, every individual with FRDA has at least one GAA expansion mutation, which has significance for therapy development.

Below are some of the research strategies now being pursued in FRDA.

Researchers are investigating therapeutic strategies that may reverse some of the abnormal processes that occur within the cells of people with FRDA.

Deficiency of frataxin causes a number of specific defects, including accumulation of iron in the mitochondria and overproduction of molecules known as “free radicals” that can damage cells. Chelation therapy has been studied as a method to soak up excess iron within cells. Antioxidant therapies, which are designed to neutralize damaging free radicals within cells, have shown promise in clinical trials.

Also under active investigation are methods to increase frataxin levels and gene replacement therapy approaches to correct the underlying defect in FRDA.

To learn more about advances in FRDA, including an overview of therapies under investigation, see the 2023 MDA clinical overview of FRDA and companion webinar here.

To learn more about clinical trial opportunities in FRDA, visit clinicaltrials.gov and search for “Freidreich’s ataxia” in the condition or disease field.

References

1. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich's Ataxia. Expert Rev Neurother. 2020 Dec;20(12):1215-1228. doi: 10.1080/14737175.2020.1821654. Epub 2020 Sep 21. PMID: 32909841; PMCID: PMC8018609.
2. Scott, V., Delatycki, M.B., Tai, G. et al. New and Emerging Drug and Gene Therapies for Friedreich Ataxia. CNS Drugs (2024). https://doi.org/10.1007/s40263-024-01113-z