AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial.

Importance: Friedreich ataxia (FA), a fatal, autosomal recessive disorder caused by pathogenic variants in the frataxin (FXN) gene, is characterized by progressive neurologic and cardiac disease, with cardiac disease being the major cause of death. Preclinical studies have demonstrated that systemic administration of AAVrh.10hFXN, an rh.10 serotype cardiotropic adenoassociated virus (AAV) vector expressing the normal human FXN coding sequence, reverses the cardiomyopathy in FXN-deficient mice. Objective: To assess the safety and preliminary efficacy of administration of AAVrh.10hFXN to adults with FA cardiomyopathy. Design, Setting, and Participants: This nonrandomized clinical trial evaluates the pooled data of 2 independent, open-label, dose-escalation trials that used the same gene therapy vector and similar clinical protocols among patients with FA cardiomyopathy at academic medical centers. Data were collected from February 22, 2022, to October 4, 2025, for trial 1 and from February 14, 2023, to September 10, 2025, for trial 2 and analyzed together from November 5, 2025, to March 12, 2026. Intervention: AAVrh.10hFXN, administered intravenously in 3 dose cohorts (1.8 × 1011, 5.6 × 1011, and 1.2 × 1012 vector genomes per kilogram of body weight). Main Outcomes and Measures: In addition to safety as the primary outcome, multiple parameters of exploratory end points were assessed, including cardiac biopsy levels of FXN protein, cardiac magnetic resonance imaging-derived left ventricular mass index (LVMI), and serum high-sensitivity (hs) troponin I. Results: Seventeen patients with FA cardiomyopathy (mean [SD] age, 25 [6] years; 11 [65%] female) were followed up for a mean (SD) of 20 (8) months. There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Other adverse events were transient, nonserious, or not treatment related. In all 8 patients with cardiac biopsy 3 months after therapy, there were higher levels of cardiac FXN (dose cohort 1, 20%; cohort 2, 81%; cohort 3, 123%). After therapy, LVMI was lower by at least 10% in 9 patients and stabilized in 8 patients. Excluding the patient with myocarditis, posttherapy values of serum hs troponin I were lower by at least 10% in 15 patients and higher by at least 10% in 2 patients. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifiers: NCT05302271 and NCT05445323.