Promising Gene Therapy for Friedreich’s Ataxia Related Heart Condition in a Mouse Model

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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A study published in the journal Nature Medicine reported a promising gene therapy approach for the heart condition associated with Friedreich’s ataxia in an animal model. The study entitled “Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia” was led by researchers at INSERM (Institut national de la santé et de la recherche médicale) in France.

Friedreich’s ataxia is a rare inherited neurodegenerative disease characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and lack of voluntary coordination of muscle movements. The disorder is caused by a mutation in a gene called frataxin (FXN), which leads to a reduction in frataxin mRNA and protein levels in different tissues. Disease onset is usually during childhood or adolescence, with an estimated incidence of one in every 50,000 births. The disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy.

Although Friedreich’s ataxia is best known for its disabling neurological features, the most common cause of death in patients is complications affecting the heart, often before the age of 35 years, as is the case of cardiomyopathy, a disease that affects the heart muscle (myocardium) making it weaker and less able to efficiently pump blood throughout the body.

The reduced frataxin protein levels in the tissues impairs the activity of mitochondria, small organelles within the cells that are responsible for energy production. This mitochondrial impairment can lead to a shortage of energy, to which the heart tissue is particularly vulnerable, potentially resulting in fatal heart failure.

In the study, researchers developed a therapeutic strategy using a viral vector [adeno-associated virus (AAV)] known to be capable of targeting and expressing therapeutic genes in heart cells. The team used this vector to deliver a normal, functional copy of the FXN gene in heart cells from mice models of Friedreich’s ataxia.

Researchers found that a single intravenous injection of the viral vector expressing FXN resulted in frataxin protein expression and fully prevented heart disease development in animals before the disease symptoms appeared. Remarkably, the team reported that this strategy also allowed a fully and very rapidly recovery of the heart condition in animals at an advanced stage of cardiomyopathy. In fact, after three weeks of treatment, mice heart was found to have become fully functional again; in addition, the heart tissue physiology and mitochondrial function in these mice was comparable to those of healthy animals.

“This is the first time that gene therapy has prompted full, lasting remission of heart disease so quickly in an animal model.” concluded the study’s co-senior author Dr. Hélène Puccio in a news release.

The research team has submitted a patent application for this gene therapy approach, and researchers involved in the study have set up a company named AAVLife in order to translate to the clinic these relevant findings. In addition, researchers are also planning to test a similar approach in tissues from the central nervous system, also affected in Friedreich’s ataxia patients.