Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia

Friedreich’s Ataxia (FA) exemplifies a critical challenge for gene therapies targeting multi-system disorders: achieving widespread therapeutic protein repletion while minimizing vector dose and systemic exposure. 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 and 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 blood-brain barrier (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. Ramachandran and colleagues describe a protein engineering approach to enhance efficacy of AAV-mediated gene therapy and demonstrate applicability for treatment of Friedreich’s Ataxia. They demonstrate broad protein repletion in mouse and NHP with a single targeted administration, establishing a scalable and generalizable platform strategy for multi-system disorders.