Therapeutic activity of a hematopoietic stem cell-delivered cell-penetrating frataxin in Friedreich's ataxia models.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to reduced frataxin, a protein essential for mitochondrial function. We developed a replacement strategy using a fusion protein containing secretion and cell-penetrating sequences fused to the frataxin precursor. In vitro studies confirmed secretion, cellular penetration, mitochondrial localization, and rescue of biochemical defects and apoptosis in cells from patients with FRDA. The therapeutic cDNA was cloned into a lentiviral vector and used to transduce hematopoietic stem and progenitor cells (HSPCs) from YG8sR mice, an FRDA model. Autologous transplantation of modified HSPCs produced stable peptide secretion in the bloodstream and delayed the onset of motor coordination symptoms, accompanied by improved biochemical and anatomical parameters. Patient-derived CD34+ HSPCs transduced with the vector differentiated normally into macrophages and secreted the peptide. These results support a cell and gene therapy strategy for long-term stabilization of FRDA.