Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Abstract

Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models

“…An optimal therapy in FRDA could consist of providing patients with sufficient frataxin amount to restore the functions of this protein. Several strategies are being developed to obtain this objective, such as gene therapy (Perdomini et al, 2014; Piguet et al, 2018), transplanting hematopoietic stem and progenitor cells (Rocca et al, 2017) or improving FXN transcription (Soragni and Gottesfeld, 2016). While advancing the development of such strategies for its application to patients, rational treatment could be considered to remove excess iron.…”

Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

“…However, no clear results supporting the benefit of any of these drugs have so far been obtained in randomized human trials (9). Other avenues for therapeutic development, however, are being pursued, including strategies aimed at increasing frataxin expression by preventing frataxin degradation (10), repeat-targeted oligonucleotides (11), and synthetic transcription elongation factors (12), together with protein replacement therapy (13), stem cell therapy (14) and gene therapy (15). Based on the knowledge that GAA⅐TTC expansion leads to heterochromatin formation and gene silencing, we have shown that members of the 2-aminobenzamide family of histone deacetylase inhibitors (HDACi) reproducibly increase FXN mRNA levels in FRDA lymphoblast cell lines (16), primary lymphocytes from FRDA patients (17), FRDA mouse models (18,19), and human FRDA neuronal cells derived from patient-induced pluripotent stem cells (iPSCs) (20).…”

Potential use of stem cells as a therapy for cystinosis

“…Most recently, because mitochondria can also be transferred via TNTs [56,[75][76][77], we also investigated if HSPC transplantation could help to prevent the mitochondrial disorder Friedreich's ataxia, a neuromuscular degenerative disorder, for which there is no treatment. We showed that HSPCs were able to migrate efficiently to all the sites of injury, i.e., the brain, spinal cord, and dorsal root ganglia (DRGs), but also to the heart and skeletal muscle, and differentiate into microglia/macrophages and deliver frataxin to neurons and myocytes [78]. Locomotor deficits and muscle weakness were prevented as well as degeneration of the large sensory neurons in DRGs, and mitochondrial dysfunction was improved in these tissues.…”