Abstract Body (Do not enter title and authors here): 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.