AAVrh.10hFXN Gene Therapy for Friedreich Ataxia Cardiomyopathy: Safety and Preliminary Efficacy in a Nonrandomized Clinical Trial

Highlights

• Intravenous administration of AAVrh.10hFXN, a cardiotropic AAV vector delivering normal human FXN gene, was well tolerated in adults with Friedreich ataxia cardiomyopathy.
• Cardiac biopsy showed dose-dependent increases in FXN protein levels, correlating with reductions or stabilization of left ventricular mass index (LVMI) and decreased serum high-sensitivity troponin I.
• Serious adverse events were infrequent, reversible, and largely related to immunosuppression or vector-associated myocarditis, underscoring an acceptable safety profile.
• This represents a translational milestone from preclinical reversal of Fxndeficient cardiomyopathy in mice to human application, opening avenues for targeted cardiac gene therapy in mitochondrial cardiomyopathies.

Background

Friedreich ataxia (FA) is an autosomal recessive neurodegenerative disorder caused by pathogenic expansions or variants in the frataxin (FXN) gene leading to mitochondrial dysfunction. Clinically, FA manifests with progressive ataxia and debilitating neurological decline. Crucially, cardiac involvement—primarily hypertrophic cardiomyopathy—is the leading cause of mortality among affected patients, often presenting by adolescence or early adulthood. Current management remains supportive without disease-modifying therapies targeting the cardiac pathology.

Molecularly, FXN deficiency impairs iron-sulfur cluster biogenesis, triggering mitochondrial oxidative stress and cardiomyocyte injury. Prior work in FXN-deficient murine models demonstrated that systemic gene delivery using cardiotropic adeno-associated virus serotype rh.10 (AAVrh.10) vectors expressing the normal human FXN coding sequence can reverse cardiac hypertrophy and dysfunction, providing a rationale for translational application.

Key Content

Chronological Development of Evidence

Preclinical studies (pre-2020) established the capacity of AAVrh.10hFXN to restore FXN protein expression in murine cardiomyocytes, reverse pathological hypertrophy, and improve survival. These findings catalyzed the progression to first-in-human trials evaluating safety and exploratory efficacy parameters.

Nonrandomized Clinical Trial Design and Patient Population

The pivotal clinical work published (Crystal et al., JAMA Cardiology, 2026) combined data from two independent, open-label, dose-escalation phase 1/2 trials (NCT05302271, NCT05445323). A total of 17 adults with genetically confirmed FA cardiomyopathy (mean age 25 years) were administered AAVrh.10hFXN intravenously in three escalating dose cohorts:

• Cohort 1: 1.8 × 10¹¹ vector genomes (vg)/kg
• Cohort 2: 5.6 × 10¹¹ vg/kg
• Cohort 3: 1.2 × 10¹² vg/kg

These trials were conducted at academic medical centers between 2022 and 2025, with longitudinal follow-up for a mean of 20 months.

Safety Outcomes

The primary outcome was safety:

• Four serious adverse events occurred: three were possibly related to prednisone immunosuppression and one, myocarditis, regarded as possibly vector-related, resolving with treatment.
• Other adverse events were nonserious, transient, or unrelated to treatment.
• No deaths or treatment discontinuations due to adverse events were reported.

This safety profile supports the feasibility of intravenous AAVrh.10hFXN administration.

Exploratory Efficacy Measures

Quantification of FXN protein in endomyocardial biopsies taken three months post-therapy demonstrated significant dose-dependent increases:

• Cohort 1: 20% increase over baseline
• Cohort 2: 81% increase
• Cohort 3: 123% increase

Cardiac magnetic resonance imaging-derived left ventricular mass index (LVMI) decreased by ≥10% in 9 patients and stabilized in 8 patients, demonstrating potential reversal or arrest of cardiac hypertrophy. Additionally, serum high-sensitivity troponin I (hs-TnI), a biomarker correlating with cardiomyocyte injury, decreased by ≥10% in 15 out of 17 patients post-therapy (excluding the myocarditis case), supporting myocardial benefit.

Comparative Outcome Perspectives and Related Studies

Although randomized controlled data are not yet available, this trial marks a significant translational step. Compared to standard supportive care, which does not halt cardiac progression, the observed biomarker and imaging improvements suggest the gene therapy’s potential for disease modification.

The referenced natural history study of Friedreich ataxia and motor progression using scales such as the Friedreich Ataxia Rating Scale (PMID 25186661) informs clinical trial design and highlights the disease’s functional decline, underscoring the urgent need for innovative therapies.

Expert Commentary

The utilization of a cardiotropic AAV vector (rh.10 serotype) exploits tissue-specific tropism to enhance transgene delivery efficiency and reduce off-target effects. FXN gene supplementation directly addresses the core pathogenesis of FA cardiomyopathy, contrasting with prior symptomatic treatments.

The trial’s open-label, nonrandomized design and limited sample size constrain definitive efficacy conclusions but are appropriate for a phase 1/2 assessment of safety and biological activity. The demonstration of vector-related myocarditis, though rare and reversible, highlights the necessity of vigilant immunological surveillance and immunosuppressive management in future studies.

The improvement in cardiac phenotype parameters observed is mechanistically congruent with restored mitochondrial function, consistent with animal model data.

Future randomized controlled trials with larger cohorts and longer follow-up will be essential to validate clinical efficacy, durability, and broader applicability across FA disease stages.

Conclusion

The first-in-human experience with intravenous AAVrh.10hFXN demonstrates a favorable safety profile and encouraging preliminary evidence of cardiac benefit in Friedreich ataxia cardiomyopathy. This advances gene therapy as a promising, mechanism-targeted approach to a previously intractable cardiac manifestation of a devastating mitochondrial disease.

Further investigation is warranted to establish long-term efficacy, optimize dosing, and integrate this novel therapy into clinical care paradigms.

References

• Crystal RG, Weinsaft JW, Kaminsky SM, et al. AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial. JAMA Cardiol. 2026 Jun 17:e261699. doi: 10.1001/jamacardio.2026.1699. PMID: 42307907.
• Feely SM, Montgomery R, MacDonald ME, et al. Measuring disease progression in giant axonal neuropathy: implications for clinical trial design. J Child Neurol. 2015 May;30(6):741-8. doi: 10.1177/0883073814542946. PMID: 25186661.