Development of an AAV-based gene therapy for the ocular phenotype of Friedreich's ataxia.

Friedreich's ataxia (FA) is a leading form of hereditary ataxia caused by autosomal recessive mutations in frataxin (FXN). GAA triplet repeat expansions lead to lower levels of FXN expression, abnormal influx of iron into mitochondria, and damage to the nervous system. Patients typically present before the second decade with loss of muscular function, speech impediments, and cardiomyopathy. At later stages, vision loss typically manifests. Work is under way to develop gene therapies that address the cardiac and CNS manifestations, but their routes of administration do not lead to efficient transduction of the retina. The purpose of this study was to develop a more direct approach for treating the ocular phenotype of FA, which includes loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fiber layer, optic nerve atrophy, and loss of visual field. We generated two novel conditional knockout (KO) models, mRx-Fxn KO and Pou4f2-Fxn KO mice, wherein Fxn is ablated in all retinal cells or RGCs, respectively, and showed that FXN deficiency led to retinal dystrophy in both models. Gene supplementation via intravitreal injection of a novel AAV2-based capsid carrying FXN partially preserved retinal structure and/or function in both models, establishing proof of concept for this therapeutic strategy.