Novel Gene Therapy Shows Safety and Early Efficacy Signals in Friedreich Ataxia Cardiomyopathy Phase 1 Trial
Key Insights
An experimental AAV-based gene therapy delivering a healthy frataxin (search) gene was well tolerated in a pooled phase 1 trial of 17 patients with Friedreich ataxia (search) cardiomyopathy.
Cardiac frataxin (search) protein levels increased in all eight biopsied patients, with dose-dependent rises of 20% to 123% across cohorts.
Left ventricular mass index decreased by at least 10% in nine patients and stabilized in eight, while troponin I levels dropped in 15 of 17 patients.
An investigational gene therapy delivering a healthy frataxin (search) (FXN) gene directly to cardiac tissue has demonstrated an acceptable safety profile and early signs of clinical benefit in patients with Friedreich ataxia (search) cardiomyopathy, according to results from a pooled phase 1 clinical trial published June 17 in JAMA Cardiology.
The non-randomized trial, led by researchers at Weill Cornell Medicine, pooled data from two independent, open-label, dose-escalation studies that used the same vector—AAVrh.10hFXN—and similar protocols. Seventeen adults with Friedreich ataxia (search) cardiomyopathy, with a mean age of 25 years and 65% female, received a single one-hour intravenous infusion across three escalating dose cohorts ranging from 1.8 × 10¹¹ to 1.2 × 10¹² vector genomes per kilogram.
"This is a fatal disease, but this is a potential therapy, and our goal is FDA-approval," said Dr. Ronald G. Crystal, the study's lead author, professor and chair of the Department of Genetic Medicine at Weill Cornell Medicine and a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center.
A Disease Driven by Energy Depletion
Friedreich ataxia (search) is an autosomal recessive hereditary disorder caused by variants in the FXN gene, leading to decreased levels of the FXN protein, which is essential for energy production in cells. As many as one in 50,000 people in the United States are diagnosed with the disease. While neurological symptoms—including problems with balance, walking, and speaking—typically begin in childhood, cardiomyopathy is the leading cause of death in up to 65% of patients.
"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," Dr. Crystal explained. Decreased FXN protein levels in the heart mean cardiac cells lack the energy to beat normally, causing muscle cells to grow and heart walls to thicken—a condition known as hypertrophic cardiomyopathy that can lead to dangerous irregular heartbeats and heart failure.
The U.S. Food and Drug Administration has approved only one drug, Skyclarys (omaveloxolone), for Friedreich ataxia (search). It slows neurological symptom progression but does not address the direct genetic cause of the disease.
Gene Therapy Design and Safety Findings
The gene therapy uses an adeno-associated virus vector to deliver a healthy copy of the FXN gene. "We put the healthy FXN gene in a virus, called adeno-associated virus, which is given intravenously and likes to travel to the heart," said Dr. Crystal.
Overall, the drug was safe, causing four serious adverse events, all of which resolved. Three of these were possibly related to prednisone, an immunosuppression drug administered to prevent patients' bodies from attacking the gene therapy. One event was a possible vector-related myocarditis at 12 months. Remaining adverse events were transient, non-serious, or unrelated to treatment.
Early Efficacy Signals
In the Lexeo Therapeutics-sponsored study, researchers performed cardiac biopsies before therapy and three months after infusion. Frataxin (search) protein levels increased in cardiac tissue in all eight biopsied patients, rising with dose from 20% in the lowest cohort to 81% and 123% in the higher cohorts.
Left ventricular mass index, an MRI measurement of heart wall thickness, decreased by at least 10% in nine patients and stabilized in eight. Serum high-sensitivity troponin I—a structural protein released into circulation when the heart is damaged and typically elevated in Friedreich ataxia (search) cardiomyopathy—dropped by at least 10% in 15 patients and rose in two, excluding the patient with myocarditis.
Using the modified Friedreich Ataxia (search) Rating Scale (mFARS), which assesses balance, coordination, speech, and limb function, researchers found that some neurological components of the disease stabilized. "But we're unsure whether this was related to the gene therapy reaching the skeletal muscle or the brain," Dr. Crystal cautioned. "That remains to be seen."
Cautions and Next Steps
The authors stressed that because the trial was small and uncontrolled, these efficacy signals are preliminary. Larger randomized trials are needed to confirm whether the therapy meaningfully alters the course of Friedreich ataxia (search). Because most patients evaluated had early cardiomyopathy, the researchers also hope to study the gene therapy in people with a wider range of heart disease severity.
The Weill Cornell Medicine study was funded by the National Heart Lung Blood Institute, while the companion study was conducted by Lexeo Therapeutics, a clinical-stage genetic medicine company founded by Dr. Crystal. Weill Cornell Medicine Enterprise Innovation played a crucial role in launching Lexeo in 2020 and later licensed additional technology to further support the clinical trial.