No disease-modifying therapies are approved for FA, and current gene therapy approaches fail to address the full disease, forcing patients to choose between cardiac protection or neurological benefit. Here, we present ‘Engineered Cross-Correction,’ in which the therapeutic protein is bioengineered for secretion, expanding the therapeutic footprint. We apply this approach to FA by engineering a secretable frataxin and delivering it via a single intra-cerebrospinal fluid (CSF) injection of an adeno-associated viral (AAV) vector equipped with a novel capsid and tissue-selective promoter. We achieved broad protein repletion across key target tissues—heart, dorsal root ganglia, and cerebellum—in mouse and non-human primate. In FA mouse models, we observed rescue of cardiac and neurological phenotypes, marking the first demonstration of dual correction with a single, minimally invasive administration. These benefits were achieved without widespread transduction, reducing vector burden and associated toxicity. Our findings establish a scalable platform that contrasts with intravenous BBB-penetrant gene delivery and offers a generalizable strategy for multi-system disorders. Beyond FA, this positions Engineered Cross-Correction as a new frontier for the next generation of gene therapies.
Tuesday, December 30, 2025
Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia
Daniel M. DuBreuil, Michael Fleming, Yashvi Parikh, Mikaela Woo, Jie Bu, Swathi Ayloo, Ingeborg M. Langohr, Dinesh S. Bangari, Christian Mueller, Shyam Ramachandran, Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia, Molecular Therapy Advances, 2025, 201661, ISSN 3117-387X, doi:10.1016/j.omta.2025.201661.
