Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

OBJECTIVE: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease. METHODS: Mice received a transplant of fluorescently tagged sex‐mismatched bone marrow cells expressing wild‐type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests. At 6 months post‐transplant, mice were euthanized for protein and histological analysis. In an attempt to augment numbers of bone marrow–derived cells integrating within the nervous system and improve therapeutic efficacy, a subgroup of transplanted mice also received monthly subcutaneous infusions of the cytokines granulocyte‐colony stimulating factor and stem cell factor. RESULTS: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and antioxidant defenses were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow–derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite‐like cells, and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow–derived cell numbers were detected after cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow–derived dorsal root ganglion satellite‐like cells. Further improvements in motor coordination and activity were evident. INTERPRETATION: Our data provide proof of concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. Ann Neurol 2018;83:779–793