Pearson Syndrome (PS) is an ultra-rare disease caused by de-novo mitochondrial DNA (mtDNA) deletions. Patients present at infancy with sideroblastic anemia and later develop a multisystem metabolic disorder, leading to death in early or late childhood. No disease-modifying treatments are available for PS. Ex-vivo enrichment of functional mitochondria into various cells has been previously demonstrated, as has inter-cellular mitochondrial transfer. In preclinical models of mitochondrial and lysosomal disorders, hematopoietic stem and progenitor cells (HSPCs) have been shown capable of carrying and transferring normal organelles into diseased tissues, thereby altering disease phenotype. Here, we show enrichment of PS-derived HSPCs with wild-type mitochondria, a process termed mitochondrial augmentation. We further report on three patients with PS treated with autologous HSPCs following ex-vivo mitochondrial augmentation.
Three patients were treated with production and safety data available, and in two patients efficacy data is available. PS-patient derived HSPCs have a diminished capacity to form colonies in vitro (median, 360 colonies per 104 cells vs. 1090 in healthy donors). HSPC colony forming capacity increased by an average of 30% after mitochondrial augmentation. Target cell dose (4×106 CD34+ cells per kg) was not reached despite two leukapheresis procedures in patients 1 and 2, who received 1.1 and 1.8 million CD34+ cells per kg recipient, respectively. Patient 3 received 2.8 million cells per kg following a single apheresis. Mitochondrial enrichment in the products was 156%, 162% and 114% for patients 1, 2 and 3. To date, the only treatment-related adverse events noted were leukapheresis related, including anemia, hypocalcemia and alkalosis.
In two patients with more than 3 months follow-up, we observed in vivo mitochondrial enrichment starting 3-4 months after cellular therapy, and throughout the follow-up period (Figure). Metabolic function of PBMCs showed improvement at 5 months post-treatment in lymphocyte ATP content, O2 consumption and TMRE:MTG ratio, indicating improved mitochondrial respiratory capacity. Improvement in mitochondrial heteroplasmy and function was in line with clinical findings: following cell therapy, no events of metabolic crisis occurred, along with normalization of a pre-treatment negative base excess in patient 1 and ongoing improvement in baseline lactate levels in patient 2. Aerobic ability and fine motor functions were superior compared to baseline in both patients. Importantly, quality of life, as measured by the International Pediatric Mitochondrial Disease Score (IPMDS), was greatly improved after treatment.
1The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3Minovia Therapeutics, Haifa, Israel 4Hematology Laboratory, Sheba Medical Center, Ramat Gan, Israel 5Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Ramat Gan, Israel