In patients with Friedreich ataxia (FA), a significant survival and cardiac benefit has been observed in adeno-associated virus (AAV)-mediated expression of frataxin (FXN) above the normal physiologic concentration attained at the 10× reference dose used in an MCK mouse model; however, toxicity is reported at higher doses.

Findings from a study designed to evaluate dose-dependent cardiac responses with intravenous administration of AAVrh.10hFXN in an MCK mouse model were presented at the 26th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT).

FA is an incurable, inherited, autosomal recessive disease, with no effective therapy available. Patients with the disorder exhibit decreased levels of FXN. Cardiac dysfunction is a major cause of early death; neurologic dysfunction is reported as well.

In individuals with FA, although heterozygotes are normal, homozygotes develop neurologic dysfunction between 5 and 15 years of age, and cardiac dysfunction between 20 and 25 years of age. In fact, two-thirds of patients with FA die of cardiac dysfunction at an average age of 37.5 years.

Read more about experimental therapies for FA

AAV-mediated gene therapy is a promising approach to the treatment of FA, based on results seen in mouse models. In the current analysis, the researchers sought to establish whether an additional benefit was associated with higher doses and higher FTX expression levels. They tested their hypothesis by administering doses of AAVrh.10FXN to 7-week-old MCK mice, in which they increased the dosing by half-log increments of 5.7×1012 genome copies (GC)/kg, 1.8×1013 GC/kg, and 5.7×1013 GC/kg.

With the original dose of 1.8×1012 GC/kg based on heterozygous cardiac FXN levels representing the target, the groups evaluated in the study were referred to as the 3.3X, 10X, and 33X dose cohorts. After vector administration, echocardiograms, cardiac and liver human FXN levels, and health and behavioral evaluations were obtained.

Results of the study showed that all of the higher-dose cohorts exhibited human cardiac FXN concentrations in excess of the target, based on the non-FA human heart escalating to 20,800±3200 ng/mg protein in the 33X cohort.

Read more about the complications of FA

Survival increased from a median of 87.5 days at the reference dose of 1.8×1012 GC/kg to a median of 119 days in the 3.3X cohort, which ultimately stabilized at 128 days in the 10X cohort. In contrast, at the 33X dose, a varied effect on survival was reported, with some mice surviving more than 200 days but some deaths occurring earlier than in the 10X cohort, which probably was indicative of toxicity at such a high dose.

According to echocardiographic findings, compared with untreated control mice, a significant dose-dependent increase in ejection fraction was detected at 11 weeks—from 18.9%±4.5% to 31.9%±2.9% in the reference dose cohort, which increased to 54.5%±9.8% in the 10X cohort. A decrease in ejection fraction was observed at the 33X dose, which is consistent with the development of cardiac toxicity.

Based on the “substantial survival and cardiac benefit in AAV-mediated expression of FTX above the normal physiologic level achieved at the 10X reference dose in the MCK mouse model of FA, but toxicity at higher doses,” the researchers noted, “this provides a rationale for ascending the dose in human clinical studies, but with caution regarding toxicity,” they concluded.


Sondhi D, Greco A, Gorman NC, et al. Dose-dependent cardiac responses to intravenous AAVrh.10hFXN treatment of the MCK murine model of Friedreich’s ataxia. Presented at the American Society of Gene & Cell Therapy (ASGCT) 26th Annual Meeting, Los Angeles, CA; May 16-20, 2023; Abstract 363.