Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.

Abstract

Friedreich's ataxia (FRDA) is a multisystemic neurodegenerative disorder caused by GAA repeat expansion in intron 1 of frataxin (FXN), resulting in FXN deficiency and mitochondrial dysfunction. Current therapies do not correct the underlying genetic defect. Here, we demonstrate that ex vivo CRISPR/Cas9 excision of the GAA expansion in hematopoietic stem and progenitor cells (HSPCs) provides durable, systemic therapy for FRDA. A single infusion of gene-edited Sca1+ HSPCs, mPPL-001, into myeloablative, humanized YG8JR mice resulted in long-term engraftment of donor-derived cells across hematopoietic and FRDA-affected tissues. mPPL-001 increased FXN expression and corrected multiple key pathogenic drivers of FRDA, including mitochondrial stress, microglial and macrophage activation, and inflammatory signaling. These coordinated effects improved motor functions, preserved cerebellar architecture, mitigated cardiac pathology, and promoted survival of insulin-producing β cells in the pancreatic islets of Langerhans. Collectively, these findings establish FXN-edited autologous HSPCs as a one-time, disease-modifying therapy for FRDA and support advancement toward a first-in-human trial.