Investigational Gene Therapy Promising for Friedreich Ataxia Cardiomyopathy: JAMA
USA: A preliminary study involving 17 patients with Friedreich ataxia cardiomyopathy has found that the investigational gene therapy AAVrh.10hFXN demonstrated encouraging early results. The therapy was generally well tolerated and showed potential to improve cardiac function by addressing the underlying frataxin deficiency that drives the disease.
The findings reported in a clinical trial published in JAMA Cardiology by Ronald G. Crystal and colleagues suggest that gene replacement therapy may offer a promising disease-modifying approach for patients with Friedreich ataxia–associated heart disease, although larger and longer-term studies are needed to confirm its safety and efficacy.
Friedreich ataxia (FA) is a rare genetic disorder caused by mutations in the frataxin (FXN) gene and is characterized by progressive neurological decline and cardiomyopathy, the leading cause of death in affected patients. Existing treatments mainly address symptoms and do not correct the underlying genetic defect.
AAVrh.10hFXN is an investigational gene therapy designed to deliver a functional FXN gene to cardiac tissue. Encouraging results from preclinical studies led researchers to evaluate its safety and potential efficacy in humans.
The analysis combined data from two open-label, dose-escalation clinical trials involving 17 adults with FA cardiomyopathy who received a single intravenous infusion of AAVrh.10hFXN. Patients were treated across three dose levels and followed for an average of 20 months.
The primary goal was to assess safety, while exploratory outcomes included cardiac frataxin protein levels, cardiac MRI measures, and blood biomarkers of heart injury.
The trial revealed the following findings:
- AAVrh.10hFXN gene therapy was generally well tolerated, with a favorable overall safety profile.
- Four serious adverse events were reported; three were potentially related to prednisone-based immunosuppression, and one involved myocarditis occurring about 12 months after treatment.
- All serious adverse events resolved, and most other adverse events were mild, transient, or unrelated to therapy.
- Cardiac frataxin protein levels increased in all eight patients who underwent cardiac biopsy three months after treatment.
- Greater increases in frataxin levels were observed at higher dose levels, indicating successful gene delivery and expression.
- Left ventricular mass index decreased by at least 10% in nine patients and remained stable in the other eight patients.
- High-sensitivity troponin I levels decreased by at least 10% in 15 patients following treatment.
- Only two patients showed an increase in troponin I levels, including the patient who developed myocarditis.
The investigators concluded that AAVrh.10hFXN was generally well tolerated and showed promising signs of clinical and biological benefit. Although the small, nonrandomized study limits conclusions on efficacy, the findings support further evaluation of this gene therapy for Friedreich ataxia cardiomyopathy. Larger controlled trials with longer follow-up are needed to confirm its long-term benefits.
Reference:
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
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