A new gene therapy appears to be safe in patients diagnosed with Friedreich ataxia cardiomyopathy, a progressive and fatal inherited cardiac disease, according to a phase 1 clinical trial led by Ronald G. Crystal, M.D., a pulmonologist at NewYork-Presbyterian and Weill Cornell Medicine and chair of the Department of Genetic Medicine at Weill Cornell Medicine. The treatment may also reduce heart damage, although further investigation is needed.
The results, which were published in JAMA Cardiology, suggest that an intravenous infusion of a healthy frataxin (FXN) gene is generally well tolerated and shows signs of early efficacy. These include a decrease in heart-wall thickness and reduced levels of troponin I, a marker of heart damage.
“This is a fatal disease, but this is a potential therapy, and our goal is FDA approval,” says Dr. Crystal.
The Cardiac Comorbidities of Friedreich Ataxia
Friedreich ataxia is an autosomal recessive hereditary disorder caused by pathogenic biallelic variants in the FXN gene, resulting in decreased levels of frataxin, a protein critical for energy production in cells. “The two most energy-consuming organs in the body are your brain and the heart, so the disease is primarily a brain and heart disease,” says Dr. Crystal.
Neurological symptoms typically begin in childhood and include problems with balance, walking, and speaking. Although progressive damage to the spinal cord, peripheral nerves, and the brain drives much of the disease burden, most people with Friedreich ataxia also develop cardiac disease, which accounts for up to 65% of mortality. In the heart, FXN deficiency impairs cellular energy production, leading to myocardial hypertrophy and progressive thickening of ventricular walls, a hallmark of cardiomyopathy.
The Food and Drug Administration has approved only one drug, omaveloxolone, to treat Friedreich ataxia; however this only slows neurological symptom progression and does not address the direct genetic cause of the disease.
“By providing the normal frataxin gene to the heart, we hope to reestablish normal cardiac function,” says Dr. Crystal. “This is important, since most patients with Friedreich ataxia have significant cardiac dysfunction.”
An illustration of hypertrophic cardiomyopathy. Friedreich ataxia is caused by variants in the FXN gene, which impairs cellular energy production and leads to progressive thickening of ventricular walls.
Phase 1 Trial Results
Building on promising preclinical research, Dr. Crystal and his colleagues studied the safety and efficacy of the gene therapy in 17 patients with Friedreich ataxia cardiomyopathy, using an adeno-associated virus vector to deliver the healthy FXN gene.
The researchers pooled data from two independent studies: nine patients were enrolled in a Weill Cornell Medicine study funded by the National Heart, Lung, and Blood Institute, while eight were treated in a study led by Lexeo Therapeutics, a clinical stage genetic medicine company founded by Dr. Crystal with the help of Weill Cornell Medicine Enterprise Innovation, which aims to accelerate the translation of scientific discoveries into patient impact.
In both studies, the patients received a one-hour infusion of the gene therapy and were evaluated from six to 36 months among three different dosing cohorts; they also underwent a 14-week immunosuppression regimen.
Friedreich ataxia is a fatal disease that we believe can be effectively treated with gene therapy. We focused on the heart disease first because it is the major cause of death.
— Dr. Ronald G. Crystal
Overall, the gene therapy was generally well tolerated. Four serious adverse events were reported, all of which were resolved, with three of them possibly related to prednisone, which were taken for immunosuppression. No patients withdrew from the study because of adverse events, and there were no deaths.
In the Lexeo study, the investigators took biopsies of the heart before therapy and three months after therapy. They found that frataxin protein levels increased in cardiac tissue in all eight patients. Both studies found reductions in left ventricular mass index — an MRI measurement of cardiac hypertrophy — suggesting potential therapeutic benefit for cardiomyopathy.
Levels of troponin I, a biomarker of heart injury, also decreased. Troponin I levels are typically high in patients with Friedreich ataxia cardiomyopathy.
Using the modified Friedreich Ataxia Rating Scale (mFARS), which assesses balance, coordination, speech, and limb function in patients, the researchers observed stabilization in some neurological measures. “But we’re unsure whether this was related to the gene therapy reaching the skeletal muscle or the brain,” Dr. Crystal adds. “That remains to be seen.”
Future research will evaluate the therapy in patients with a broader spectrum of heart disease severity.
“Friedreich ataxia is a fatal disease that we believe can be effectively treated with gene therapy,” says Dr. Crystal. “We focused on the heart disease first because it is the major cause of death. Future studies will include gene therapy for the nervous system manifestations of the disease.”
Dr. Ronald G. Crystal is a founder, Chief Scientific Advisor, consultant, equity holder, and board observer of Lexeo Therapeutics and is an inventor on intellectual property assigned to Weill Cornell Medicine.
The Weill Cornell Medicine trial was supported by funding from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, through grant NHLBI HL151355. The Lexeo trial was funded by Lexeo Therapeutics, Inc.
A version of this article originally ran on Weill Cornell Medicine's newsroom.
