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

Abstract

ObjectiveFriedreich'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.MethodsMice 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.ResultsTransplantation 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.InterpretationOur 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

Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia

“…Intrathecal delivery of bone marrow-derived mesenchymal stem cells, both autologous and allogeneic, to the YG8R FRDA mouse model has been reported to increase frataxin expression in the DRG, to increase the levels of antioxidant enzymes, and to improve motor function [127]. Similar findings have been reported by Kemp and colleagues [130], and these investigators have also shown that stem cell-derived factors [128], as well as the cytokines granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) [131] have similar effects of ameliorating the disease phenotype in the YG8R FRDA mouse model, and each of these treatments induced frataxin expression in affected tissues. As to how stem cells increase frataxin levels, Rocca and colleagues recently reported the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to neurons and muscle myocytes in the YG8R mouse model [129].…”

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia

“…Abundant HSPCs engrafted into affected tissues and differentiated into microglia in brain and spinal cord, and macrophages in DRG, heart and muscle, and led to frataxin transfer to the diseased neurons and myocytes. Another study ( Kemp et al, 2018 ) subsequently reported similar results where transplantation of wild type bone marrow (BM) cells to YG8R FRDA mice improved motor coordination, rescued neurobehavioral deficits and resulted in engraftment of bone marrow-derived macrophages/microglia in DRG, spinal cord and cerebellum. Altogether, these data represent the proof of concept that the different complications associated with FRDA could be treated by a HSPC transplantation.…”

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich’s ataxia

“…Release of haematopoietic stem and progenitor cells into the peripheral circulation may have important therapeutic implications in FA. Our studies investigating bone marrow transplantation strategies in humanised FA mouse models have revealed that G-CSF can stimulate the recruitment of bone marrow cells to areas of FA-associated pathology to promote nerve cell repair 10 .…”

“…Continued research and technological advances in regenerative medicine have increased interest in developing neuro-reparative stem cell-based therapies for people with FA. Using a humanised murine model of FA we demonstrated that treatment with the stem cell mobilising cytokines granulocyte-colony stimulating factor (G-CSF) and stem cell factor had pronounced effects on frataxin levels within the nervous system and improved clinical, biochemical and pathological parameters associated with the disease 10 , 11 . Moreover, we have also shown that these agents had neuroprotective effects in FA, increased stem cell mobilisation to sites of pathology and stimulate neural repair 10 .…”