Mitochondrial Augmentation Therapy: From Preclinical Studies to First in Man Treatment of Patients with Mitochondrial Disease

Mitochondrial diseases caused by mtDNA deletions or mutations are debilitating and life-threatening, yet no effective pharmacologic treatments are available and treatment is symptomatic. We and others demonstrated that mitochondria can enter cultured cells in a dose-dependent process, fuse to the endogenous network and maintain functionality. We utilized this process to develop mitochondrial augmentation therapy (MAT) for treatment of Pearson Syndrome (PS), a debilitating rare disease caused by a de novo deletion in the mtDNA, associated with multiple organ involvement and early death. We optimized mitochondrial uptake by hematopoietic stem and progenitor cells (HSPCs). Preclinical mouse models demonstrated the ability of augmented HSPCs to home not only to bone marrow but to non-hematopoietic tissues, possibly enabling tissue-specific functional rescue.

We hypothesized that autologous patient-derived HSPCs, reinfused after ex-vivo enrichment with normal mitochondria isolated from maternal blood cells, may propagate wild-type mtDNA in multiple organs and improve patient wellbeing. Under a compassionate use program, we treated three PS patients. Aerobic ability and muscle strength, and quality of life measured by the International Pediatric Mitochondrial Disease Score questionnaire improved in all patients. In addition, specific improvements per patient were noted based on different organ involvement, including improvements in growth and kidney function. An FDA-cleared clinical trial is ongoing to assess the potential of MAT to reverse or slow disease progression in patients with PS. We are currently investigating whether the mechanism by which MAT exerts clinical efficacy involves inter-cellular mitochondrial transfer, HSPC homing to non-hematopoietic tissues, cytokine or mitochondrial-derived peptide secretion, or immunomodulation.