US FDA Grants Expanded Approval of ELEVIDYS Gene Therapy for DMD Patients Ages 4 and Above

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Friedreich's Ataxia (FA)


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 opened the door to a much better understanding of FA and new avenues for treatment development. MDA funding led to the discovery of the frataxin gene.

Although two types of FA-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 FA 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 FA 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 FA has at least one GAA expansion mutation, which has significance for therapy development.

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


Antioxidants are designed to offer some protection against cell damage by chemicals known as free radicals and to enhance production of energy from cellular mitochondria.

The antioxidant idebenone has been shown to be safe and well-tolerated in a number of clinical trials in FA. Unfortunately, benefits have been modest, at best.

Idebenone is similar to coenzyme Q10, a naturally occurring molecule. In 2010, a large-scale trial of idebenone in people with FA was conducted at several European centers but did not show benefit on neurological rating scales. A previous large-scale trial of idebenone in children with FA likewise did not show benefit. However, an earlier, phase 2 study, lasting six months and including 48 people, showed a statistical trend toward dose-related improvements in neurological function in those who received idebenone.

New antioxidant compounds are in development. In April 2011, Intellect Neurosciences said it wanted to develop its experimental antioxidant compound OX1 (Oxigon) for FA.


In June 2011, Edison Pharmaceuticals announced preliminary results from a 28-day phase 2a clinical trial of its experimental compound EPI-A0001 in FA. Edison said there was significant improvement in neurological function as assessed by the Friedreich's Ataxia Rating Scale in people who received the drug compared to those who received a placebo. The company said additional trials will be required to determine the safety and effectiveness of EPI-A0001. The drug is designed to improve energy production in mitochondria.


Frataxin production may be stimulated through the use of erythropoietin, a naturally occurring protein.

In 2010, an Austrian research team reported results of a small "proof-of-concept" trial in which 12 people with FA received erythropoietin injections three times a week for eight weeks. Eight of the 10 trial participants showed stable increases of frataxin levels, with individual increases ranging from 15 to 63 percent. Ataxia severity showed a 6 percent improvement in study participants.

Carbamylated erythropoietin, a derivative of erythropoietin, has been shown to increase frataxin levels in FA-affected cells without the unwanted added effect of stimulating blood-cell production, as erythropoietin does, making it a potential alternative for drug development for FA.

Gene therapy

One approach to treating FA would be to supply functional frataxin genes or protein molecules to the person with FA through the insertion of functional genes to compensate for nonfunctional ones.

Various gene therapy-based strategies hold the potential to benefit individuals with FA. Although it’s relatively early in the game, a limited number of studies in mice and human cells have yielded some encouraging results.

In a 2005 study, researchers used lentiviral or adeno-associated viral (AAV) vectors to carry the human frataxin gene into fibroblasts (cells that mature into a variety of connective tissue types) from FA patients. (A vector is a delivery vehicle for therapeutic genes.) Results included increased frataxin protein levels and a reduction in the treated cells’ sensitivity to oxidative stress.

A 2007 study analyzed the feasibility of gene insertion via the emptied-out shell of the herpes simplex virus type 1 (HSV-1), partnered with a stretch of DNA called an amplicon that helps the vector target a specific cell type. Results in FA-affected mice and human cells showed highly efficient DNA transfer and increased levels of frataxin production.

Similar positive results in 2007 came from a Spanish study in which mice were engineered so that researchers could eliminate, or “knock out,” frataxin activity specifically in motor neurons. The mice developed neurological symptoms after four weeks, but achieved full recovery in as few as four weeks after receiving injections of HSV-1 amplicon vectors carrying DNA that codes for human frataxin.

A Spanish study published in 2010 describes the successful use of artificial chromosomes and similar constructs called episomes to act as vectors for transporting genes to their targets.

HDAC inhibition

The biotechnology company Repligen has received MDA support for development of an experimental treatment for FA known as histone deacetylase (HDAC) inhibition. HDAC inhibitors keep "read me" signals called acetyl groups on genes. Cells interpret these signals to mean that a gene is available to be "read" and used for protein production. HDAC inhibitors may make it possible to stimulate frataxin production despite the presence of a mutation in the gene.

Iron chelation

Iron chelation — the trapping of harmful, unbound iron — is a possible therapy for FA. A 2008 study in research mice that didn't produce frataxin in their hearts showed that iron chelation significantly decreased iron levels in the heart and limited the harmful increase in the size of the cardiac muscle normally seen in frataxin-deficient mice.

An ongoing study to evaluate the effects of an iron chelator called deferiprone in people with FA in Europe may increase understanding of whether iron chelation should be part of an FA therapy regimen.

There is some evidence that combining an antioxidant with an iron chelator may be beneficial. A 20-person study for which results were announced in 2010 found that a combination of idebenone and deferiprone had a "stabilizing effect" on neurological function and reduced abnormal heart-muscle enlargement in people with FA who received the two-drug combination for 11 months.

Protein therapy

Another approach to treating FA involves inserting new frataxin protein molecules. Recent research has shown that the frataxin protein can be modified so that it can cross membranes and get to the right place in cells, themitochondria.

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