Stem Cells Reverse Damage Caused by Incurable Neuromuscular Disease

Being able to reverse the damage caused by neurodegenerative diseases is the ultimate goal of many research endeavors within the neuroscience field. Now, researchers at the University of California San Diego (UCSD) School of Medicine report that a single infusion of wildtype hematopoietic stem and progenitor cells (HSPCs) into a mouse model of Friedreich’s ataxia (FA) measurably halted cellular damage caused by the degenerative disease.

Findings from the new study – published recently in Science Translational Medicine in an article entitled “Transplantation of Wild-Type Mouse Hematopoietic Stem and Progenitor Cells Ameliorates Deficits in a Mouse Model of Friedreich’s Ataxia” – suggest a potential therapeutic approach for a disease that currently is considered incurable.

FRDA is a rare, inherited, degenerative neuromuscular disorder that initially impairs motor function, such as gait and coordination, but can lead to scoliosis, heart disease, vision loss, and diabetes. Cognitive function is not affected. The disease is progressively debilitating, and ultimately requires full-time use of a wheelchair. Previous studies have shown that FRDA is caused by reduced expression of a mitochondrial protein called frataxin (FXN) due to a two mutated or abnormal copies of the FXN gene. In the current analysis, the UCSD team used a transgenic mouse model that expresses two mutant human FXN transgenes and exhibits the resulting progressive neurological degeneration and muscle weakness.

“We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA,” the authors wrote. “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.”

HSPCs derived from bone marrow have become a primary vehicle for efforts to replace or regenerate cells destroyed by a variety of diseases. Previous research by the study authors had shown that transplanting wild-type or normal mouse HSPCs resulted in long-term kidney, eye, and thyroid preservation in a mouse model of cystinosis, another genetic disorder.

In this study, the investigators transplanted wild-type HSPCs into an FRDA mouse model, reporting that the HSPCs engrafted and soon differentiated into macrophages in key regions of the mice’s brain and spinal cord where they appeared to transfer wild-type FXN into deficient neurons and muscle cells.

“Transplantation of wild-type mouse HSPCs essentially rescued FRDA-impacted cells,” noted senior study investigator Stephanie Cherqui, Ph.D., associate professor in the UCSD School of Medicine Department of Pediatrics, “Frataxin expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.”

While the researchers were excited by their findings, they noted that the mouse model is not a perfect mirror of human FRDA. Disease progression is somewhat different, and the precise pathology in mice is not fully known. However, the researcher’s findings are encouraging and point toward a potential treatment for a disease that currently has none.

“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 authors concluded.