Introduction: Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder caused by an abnormal GAA repeat expansion within the frataxin (FXN) gene, which encodes a mitochondrial protein essential for iron-sulfur cluster biosynthesis and cellular energy production. FXN deficiency results in a multi-system disorder marked by progressive ataxia, sensory neuropathy, and cardiomyopathy. There remains a need for disease-modifying therapies that address both the cardiomyopathy and the neurologic manifestations which are the main determinants of morbidity and disability in FA.
Hypothesis: AAV-mediated gene replacement therapy can safely increase FXN expression in disease-relevant tissues and modify the course of FA.
Approach: SGT-212, Solid Biosciences’ investigational AAV gene therapy for FA, expresses full-length, human FXN under a ubiquitous promoter. Preclinical evaluation of SGT-212 assessed neurologic and cardiac outcomes in conditional Fxn knockout mouse models targeting the nervous system (nKO) and heart (cKO). Long-term safety and biodistribution were assessed in non-human primates (NHPs) to support a first-in-human clinical trial using a dual route of administration via intraparenchymal dentate nucleus (IDN) and intravenous (IV) infusions. This multisystem, dual route approach was designed to target the neurologic, cardiac and systemic manifestations of FA.
Results: In Fxn nKO mice, SGT-212 IV administration resulted in increased number of FXN+ neurons and dose-dependent improvements in lifespan and sensorimotor function. In Fxn cKO mice, IV administration led to increased FXN protein expression in cardiac tissue, prolonged survival and dose-dependent improvements in cardiac function and structure. In NHPs, dual IDN and IV administration was well tolerated throughout a 12-month study duration. No adverse findings were observed across multiple dose levels. Robust FXN expression was observed in key FA target tissues including DRG, dentate nuclei, and myocardium.
Conclusions: These nonclinical studies demonstrate that a one-time administration of SGT-212 increases FXN expression in disease-relevant tissues, improves neurologic and cardiac phenotypes in mouse models, and is well tolerated in NHPs. Altogether, this positive, nonclinical data package supports the Phase 1b FALCON trial (NCT07180355), a first-in-human evaluation of SGT-212, which is actively screening participants.