Journal of Clinical Investigation· 2026Q1
Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich’s ataxia mice
- 1citations
- Q1SCImago
- 2026year
Short summary
CRISPR/Cas9 editing of hematopoietic stem and progenitor cells (HSPCs) to remove GAA repeat expansions in the FXN gene durably rescued multisystemic pathology in Friedreich's ataxia mice.
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Key points
- CRISPR/Cas9 editing of HSPCs removed GAA repeat expansions in the FXN gene, increasing FXN expression in FRDA mice.
- Gene-edited HSPCs engrafted long-term across hematopoietic and affected tissues.
- Therapy corrected mitochondrial stress, microglial/macrophage activation, and inflammatory signaling.
- Observed improvements included motor function, cerebellar architecture, cardiac pathology, and pancreatic beta cell survival.
AI-generated from the title and abstract; the full text is not read.
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.
The authors' abstract, as published at the source. Journal of Clinical Investigation, 2026 · DOI ↗
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Field: Cellular and Molecular Neuroscience
Cellular and Molecular NeuroscienceNeuroscience