Abstract 4366785: Efficacy and Safety of a Novel AAV <i>FXN</i> Gene Therapy (SGT-212) for the Treatment of Friedreich’s Ataxia

Introduction: Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder caused by variants in the frataxin ( FXN) gene, leading to mitochondrial dysfunction and impaired energy metabolism. Cardiomyopathy is the leading cause of death in FA and represents a critical therapeutic target alongside progressive neurological decline. Hypothesis: AAV-mediated gene replacement therapy can safely restore FXN expression in disease-relevant tissues and modify the course of FA. Approach: A gene therapy candidate (SGT-212) utilizing an AAVhu68 capsid and a ubiquitous promoter to express human FXN was developed. SGT-212 was administered using a dual route of administration via intravenous (IV) and intraparenchymal dentate nucleus (IDN) infusions. Cardiac and neurologic efficacy was evaluated in conditional Fxn knockout mouse models (cKO and nKO, respectively). Long-term safety and biodistribution were assessed in non-human primates (NHPs). Results: In Fxn cKO mice, a single IV dose led to dose-dependent improvements in cardiac function (assessed by echocardiography), histopathology, and survival. FXN protein levels and the number of FXN+ cardiomyocytes increased in a dose-dependent manner. In Fxn nKO mice, a single IV administration improved sensorimotor function (Neuroscore, RotaRod), extended lifespan, and restored FXN expression in dorsal root ganglia. In NHPs, the gene therapy was administered via dual IV/IDN routes and monitored for 12 months. SGT-212 treatment was well tolerated across dose levels with no adverse findings. Robust expression of FXN was observed in key target tissues, including myocardium, DRG, and dentate nuclei. Conclusions: These nonclinical studies demonstrate that a one-time administration of SGT-212 can restore FXN expression in disease-relevant tissues, improve cardiac and neurologic phenotypes in mouse models, and is well tolerated in NHPs. These findings support advancement to a Phase 1b clinical trial using combined IV/IDN administration.