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

Friedreich’s ataxia (FRDA) is an inherited disease that progressively affects movement and coordination and can also cause heart disease and diabetes. It is caused by an abnormal expansion of a repeated DNA sequence in the frataxin gene, reducing production of frataxin, a protein essential for mitochondrial function. This deficiency disrupts cellular energy production,and contributes to inflammation and tissue damage across multiple organs. In this study, we evaluated a stem cell gene-editing approach in mice carrying the human FRDA mutation. Using CRISPR/Cas9, we removed the expanded DNA sequence from blood-forming stem and progenitor cells, which produce blood and immune cells. These edited cells, called mPPL-001, are the mouse counterpart of the investigational human therapy PPL-001. Following a single infusion, cells derived from the transplanted stem cells persisted in the bone marrow and reached multiple disease-affected organs. Treatment increased frataxin expression and improved walking patterns in diseased mice while preserving neurons and tissue structure in the cerebellum, a brain region involved in movement and coordination. Molecular analyses showed improvements in pathways involved in mitochondrial maintenance, cellular stress responses, DNA repair, and regulation of gene activity, alongside reduced inflammatory signaling. In the heart, treatment increased mitochondrial frataxin, preserved mitochondrial structure, improved heart chamber dimensions and reduced inflammation. In the pancreas, treatment increased the abundance of insulin-producing cells and promoted a less inflammatory tissue environment. Together, these findings demonstrate that gene-edited blood-forming stem cells can address multiple organs that are affected by the disease and provide sustained benefits across the brain, heart, and pancreas. They support further development of PPL-001 as a potential one-time therapy using a patient’s own gene-edited stem cells