Gene Therapy Reduces LV Mass in Friedreich Ataxia Cardiomyopathy

Intravenous administration of AAVrh.10hFXN, an adeno-associated virus vector encoding normal human frataxin, was associated with reductions in left ventricular mass index (LVMI) and high-sensitivity troponin I (hs-cTnI) levels in patients with Friedreich ataxia (FA) cardiomyopathy, according to pooled data from 2 nonrandomized open-label dose-escalation trials published in JAMA Cardiology.

“In an open-label, dose-ranging, nonrandomized clinical trial of 17 patients, intravenous administration of AAVrh.10hFXN was associated with minimal toxic effects, reduced cardiac magnetic resonance imaging assessment of left ventricular mass index, and reduced serum high-sensitivity troponin I level,” wrote the researchers of the study.

The pooled analysis combined results from a phase 1A investigator-initiated trial at Weill Cornell Medicine (NCT05302271) and a phase 1/2 industry-sponsored trial by Lexeo Therapeutics (NCT05445323), evaluating the vector as LX2006. Across 17 patients with a mean age of 25 years (65% female), the primary end point was safety. Exploratory efficacy end points included cardiac MRI–derived LVMI, hs-cTnI, and cardiac biopsy levels of frataxin protein. Patients were followed for a mean of 20 months.

Cardiomyopathy: There Is Currently No Approved Therapy

FA is caused by pathogenic GAA trinucleotide expansions in the FXN gene that suppress frataxin expression, impairing mitochondrial iron-sulfur cluster assembly and reducing adenosine triphosphate generation. Cardiomyopathy accounts for 60% to 65% of deaths in this population. Currently, omaveloxolone (Skyclarys; Biogen) is the only FDA-approved treatment for FA, indicated for the neurologic manifestations of the disease; no therapy is approved specifically targeting the cardiomyopathy.

Three ascending dose cohorts were evaluated: 1.8 × 10¹¹, 5.6 × 10¹¹, and 1.2 × 10¹² vector genomes per kilogram. All 8 patients who underwent cardiac biopsy at 3 months post infusion demonstrated increases in cardiac frataxin protein, with mean increases of 20%, 81%, and 123% across dose cohorts 1, 2, and 3, respectively. Qualitatively, 9 of 17 patients showed LVMI reductions of at least 10%, and 8 patients showed stabilization. Using a linear mixed-effects model excluding 1 patient who developed myocarditis at month 12, LVMI declined at a mean rate of −0.50 g/m² per month (95% CI, −0.71 to −0.29). Hs-cTnI levels decreased in 15 of 17 patients by at least 10%, and the mixed-effects model excluding the patient with myocarditis showed a mean monthly reduction of −13.7 ng/L (95% CI, −20.9 to −6.4).

The Gene Therapy Was Generally Well Tolerated

The therapy was generally well tolerated. Four serious adverse events were reported: 1 case of asymptomatic myocarditis at month 12, considered possibly vector-related and resolving with corticosteroids, and 3 events possibly related to prednisone immunosuppression (streptococcal A infection, pneumonia, and chest pain requiring hospitalization). No deaths occurred, and no patients withdrew due to adverse events. Liver enzyme abnormalities and complement activation were not observed as significant safety signals.

The authors noted that modified Friedreich Ataxia Rating Scale neurologic scale scores stabilized over follow-up, which they speculated may relate to the vector’s known distribution to skeletal muscle, a finding they flagged as warranting evaluation in future controlled studies. Limitations include the small sample, nonrandomized design, absence of a contemporaneous control group, and predominance of patients with early-stage cardiac disease.

FA cardiomyopathy differs from sarcomeric hypertrophic cardiomyopathies; the hypertrophy in FA is associated with mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression, and patients are at risk for atrial arrhythmias, apoptosis, fibrosis, and heart failure leading to premature death. This distinction has historically complicated management, as standard heart failure guidelines do not account for the metabolic etiology of the disease.²

“Findings of this nonrandomized clinical trial suggest that intravenous administration of AAVrh.10hFXN was well tolerated and may be a potential treatment for FA cardiomyopathy, as evidenced by preliminary improvement in exploratory efficacy end points,” wrote the researchers.

References

1. Crystal RG, Weinsaft JW, Kaminsky SM, et al. AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich ataxia: a nonrandomized clinical trial. JAMA Cardiol. Published online June 17, 2026. doi:10.1001/jamacardio.2026.1699
2. Payne RM. Cardiovascular research in Friedreich ataxia: unmet needs and opportunities. JACC Basic Transl Sci. 2022;7(12):1267-1283.