Gene Therapy Associated With Neurologic Stabilization in Friedreich Ataxia
KEY TAKEAWAYS
- Exploratory mFARS findings remained stable during a mean 20 months of follow-up in adults with Friedreich ataxia treated with investigational AAVrh.10hFXN gene therapy.
- The analysis included 17 adults with genetically confirmed Friedreich ataxia and cardiomyopathy, 11 of whom were nonambulatory at baseline.
- Four serious adverse events occurred, including 1 case of myocarditis considered possibly related to the vector; all resolved.
Systemic AAVrh.10hFXN gene therapy was associated with stable neurologic disease scores in adults with Friedreich ataxia (FA), according to exploratory findings from 2 small, nonrandomized trials. Although the studies primarily evaluated treatment of FA cardiomyopathy, investigators also followed neurologic outcomes longitudinally using the modified Friedreich Ataxia Rating Scale (mFARS).
Investigators pooled data from 2 open-label, dose-escalation trials involving 17 adults with genetically confirmed FA and cardiomyopathy. Participants received intravenous AAVrh.10hFXN, also referred to as LX2006, at doses ranging from 1.8 × 10¹¹ to 1.2 × 10¹² vector genomes/kg. Mean age was 25 years, 11 participants (65%) were female, and mean follow-up was 20 months. Eleven participants were nonambulatory at baseline. Safety was the primary outcome, with neurologic outcomes assessed exploratorily using mFARS.
What Stood Out for Neurologists
- mFARS scores remained stable during follow-up after AAVrh.10hFXN administration. Investigators contrasted this pattern with previously published natural history data showing progressive mFARS worsening in untreated FA.
- The studies did not include a contemporaneous untreated control group, limiting conclusions about whether treatment accounted for the observed mFARS trajectory.
- The authors noted that little systemically administered AAVrh.10 reaches the brain, whereas vector distribution is substantial in skeletal muscle. They proposed skeletal muscle FXN delivery as a potential contributor to the mFARS findings, although this mechanism remains unconfirmed.
- Several participants received omaveloxolone for neurologic manifestations of FA during the study.
AAVrh.10hFXN remains investigational. The authors identified controlled evaluation of neurologic and musculoskeletal outcomes as an area for future study.
Source:
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;11(8):709-718. doi:10.1001/jamacardio.2026.1699