A gene therapy approach to increase the amount of the critical frataxin protein shows that correcting only half of the heart muscle cells, or cardiomyocytes, is enough to fully restore the cardiac function in a mouse model of Friedreich’s Ataxia (FA)
The study, “Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms,” was published in the journal Human Molecular Genetics.
FA is characterized by reduced level of the frataxin protein due to a mutation in both copies of the FXN gene. Frataxin deficiency causes a deficit in iron sulfur clusters (Fe-S, crucial for functions such as iron metabolism and energy production in cells), impaired activity of specific enzymes, dysfunction of mitochondria (the cellular power plants), and iron overload.
Cardiac dysfunction and anomalies are common in patients with FA. The research team previously showed that delivering the normal FXN gene to cardiac cells via modified, harmless viral vectors prevents and rapidly reverses cardiac alterations in a mouse model (Mck) of cardiomyopathy (heart muscle disease) in FA.
These mice showed levels of frataxin 24-fold greater than normal, which may carry safety issues in clinical trials and may not be required in patients, as asymptomatic carriers of the mutated FXN gene have nearly half the normal amount of protein. As such, finding the therapeutic thresholds for these vectors in the heart is key, the team from France considered.
Aiming to address this, the scientists used the MCk mouse model to evaluate the extent of cardiac function rescue following the administration of lowering doses of an adeno-associated viral vector (AAV) carrying the human FXN gene. To assess how disease progression affected therapeutic success, the researchers used mice with early (five weeks of age) or advanced (seven weeks) cardiac dysfunction.
The team further characterized the vector’s pharmacological profile in the heart, and established the minimal cardiac biodistribution — meaning the vector copies per cell (VCN) and the percentage of cardiomyocytes rescued — to restore cardiac function.
The mice were given one of six 2-2.5-fold decreasing doses and were followed for seven to eight weeks. When treated with 5 x 1013 and 2.5 x 1013 vg/kg doses at five weeks, the mice survived beyond the median survival of untreated mice, and showed normal body weight and echocardiography parameters.