FXN Gene Therapy Treats Heart Problems in New FA Mouse Model

A gene therapy that delivers a healthy version of the FXN gene can correct heart problems in a new mouse model with cardiac-specific symptoms of Friedreich’s ataxia (FA), a study reports.

This animal model more accurately mirrors the early cardiac abnormalities seen in FA patients, the researchers wrote, providing new opportunities to study FA symptoms and investigate disease-modifying therapies.

The study, “Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich’s Ataxia Corrected by AAV-mediated Gene Therapy,” was published in the journal Human Gene Therapy.

FA is a rare genetic disease caused by mutations in the FXN gene, and a consequent deficiency in the frataxin protein, which is essential for mitochondria, the energy-producing structures of cells, to work as they should.

Frataxin deficiency has a pronounced effect on heart muscle cells, which have the highest mitochondria density of all cells in the body, damaging heart muscles and impairing their function.

While neurological symptoms affect mobility and speech, severe heart disease is the most frequent cause of mortality among FA patients. However, studies of FA-related cardiac symptoms are limited by mouse models that do not accurately mirror the disease’s progression in humans.

Mouse models of FA with cardiac deficits rapidly decline in health, and become terminal within two months, the researchers reported. By contrast, severe cardiac disease typically does not manifest in people with FA for decades, likely due to their relatively limited mobility, which reduces oxygen demands and cardiac stress.

Researchers at Weill Cornell Medical College developed a mouse model of FA with cardiac abnormalities that more closely resembled the disease in people. Their new model, alpha Myhc, was generated by selectively expressing a defective FXN gene in cardiac tissue, resulting in a deficiency of FXN protein specifically in the heart. 

To characterize the model’s clinical and physiological features, researchers measured FXN levels and the activity of protein complexes involved in mitochondrial energy production pathways. Cardiac symptoms were induced chemically with dobutamine, a cardiac stimulant, and physically with treadmill exercise, and assessed by measuring the heart muscle’s ability to contract. 

FXN protein levels in the heart tissue of alpha Myhc mice were 51% lower than in healthy control animals, while no difference was observed in skeletal muscle, suggesting the mouse model selectively depleted the protein in heart tissue.

The reduction in FXN levels corresponded to a 56% decrease in the activity of energy-producing mitochondrial complexes in the heart cells of alpha Myhc mice.

At rest, these mice were normal and similar in cardiac function to controls. But they exhibited a poorer response to chemically induced stress compared with controls, with a significant reduction in stress-induced heart muscle contraction.

When subjected to exercise-induced stress on a treadmill, alpha Myhc mice failed to keep pace with controls, spending significantly less time above the treadmill midpoint.

The alpha Myhc mice were then treated with healthy copies of the FXN gene, delivered specifically to heart tissue via adeno-associated viral (AAV) vectors, called AAVrh.10hFXN. Of note, AAV vectors are small, harmful viruses engineered to carry gene therapies.

After treatment, the animals’ heart function in stress conditions was similar to that of control mice. Their heart muscle contractility after chemically induced stress was indistinguishable from healthy controls, and they performed significantly better on the treadmill, keeping pace with controls and outpacing untreated alpha Myhc mice.

“With chemical- and exercise-induced stress, these mice exhibit significant cardiac dysfunction that can be effectively treated with an adeno-associated virus (AAV)-gene therapy,” the researchers wrote. “This observation provides proof of concept for AAVrh.10hFXN therapy for cardiac manifestations of FA.”

The alpha Myhc mouse model and the successful representation of stress-induced cardiac symptoms may also facilitate future research into long-term cardiac issues related to FA that more accurately represent the disorder in patients.

“The complexity of single gene disorders often complicates the strategies approached to clinical gene therapy. The demonstration by these authors that FA may require a systemic delivery method to correct both the cardiac and neurologic manifestations of the disease could be of critical importance in future FA gene therapy,” Terence R. Flotte, MD, Human Gene Therapy‘s editor-in-chief, said in a press release.