Mitochondrial Augmentation Therapy: Mitochondrial Enrichment of Hematopoietic Stem Cells in Patients with Mitochondrial Disease

Mitochondrial diseases caused by mtDNA deletions or mutations are debilitating and life-threatening, yet to date all treatment is symptomatic. We have demonstrated that exogenous mitochondria can enter cells in culture, augmenting endogenous mitochondrial function and content and fusing with the endogenous mitochondrial network. The process of mitochondrial uptake, which we term mitochondrial augmentation, was optimized to allow a high proportion of CD34+ HSPCs to uptake these organelles.

We performed first-in-man trials in four patients with non-inherited mitochondrial deletion syndromes, enriching patient-derived HSPCs using ex-vivo mitochondrial augmentation with wild-type mitochondria provided from their mother’s white blood cells. Safety and efficacy data for over 29 months post-mitochondrial augmentation therapy (MAT) is currently available.

MAT cell therapy was demonstrated to be safe, and quality of life, as measured by the International Pediatric Mitochondrial Disease Score (IPMDS) questionnaire, improved after treatment. In addition, aerobic ability and muscle strength assessments in Pearson Syndrome patients were superior post-treatment compared to baseline, and EEG was improved in the Kearns-Sayre Syndrome patient treated. While it is known that there is a high variability in presentation and progression of patients, individual improvements per patient were noted.

Together, these clinical data suggest that mitochondrial augmentation therapy, in which HSPCs are augmented with organelles encoding a non-mutated version of the mtDNA sequence, is a potential method to diminish disease progression in patients with mtDNA disorders. An FDA-cleared phase I/II trial is currently underway, and an allogeneic product is under development for inherited mitochondrial disorders.