Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.
4 affiliations
- 1Department of Pediatrics, Division of Genetics, and.
- 2Department of Pathology, University of California, San Diego, La Jolla, California, USA.
- 3Penn/CHOP, Friedreich's Ataxia Center of Excellence, Philadelphia, Pennsylvania, USA.
- 4Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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.
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BibTeX
@article{sivakumar2026edited,
title = {{Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.}},
author = {Anusha Sivakumar and Alexis N Corl and Keneth Jordan Muñoz and Subhashini Arumugam and Betul B Gunes and Angelyn B Solis and Rishika Murthy and Lilas Rony El-Hachem and Donald P Pizzo and Ian A Blair and Teerapat Rojsajjakul and Clementina Mesaros and Xinlong Wan and Joseph N Rainaldi and Rafael A Badell-Grau and Veenita Khare and Kevin Eric Thai and Kavya Biederman and Stephanie Cherqui},
journal = {The Journal of clinical investigation},
year = {2026},
month = oct,
doi = {10.1172/jci209546},
url = {https://europepmc.org/article/MED/42878077},
note = {CC BY},
}
RIS
TY - JOUR
TI - Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.
AU - Anusha Sivakumar
AU - Alexis N Corl
AU - Keneth Jordan Muñoz
AU - Subhashini Arumugam
AU - Betul B Gunes
AU - Angelyn B Solis
AU - Rishika Murthy
AU - Lilas Rony El-Hachem
AU - Donald P Pizzo
AU - Ian A Blair
AU - Teerapat Rojsajjakul
AU - Clementina Mesaros
AU - Xinlong Wan
AU - Joseph N Rainaldi
AU - Rafael A Badell-Grau
AU - Veenita Khare
AU - Kevin Eric Thai
AU - Kavya Biederman
AU - Stephanie Cherqui
PY - 2026
DA - 2026/10/15
JO - The Journal of clinical investigation
DO - 10.1172/jci209546
UR - https://europepmc.org/article/MED/42878077
AB - 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.
SN - 0021-9738
SN - 1558-8238
ER -