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Abstract Currently the only curative treatment option for patients with myelodysplastic syndromes (MDS) is allogeneic bone marrow transplant. However, allogeneic transplant is not feasible for the majority of MDS patients. Several studies have identified that mitochondrial dysfunction contributes to the pathogenesis and clinical severity of MDS. To this end, mitochondrial augmentation technology has been recently developed whereby patient hematopoietic stem/progenitor cells (HSPCs) are collected and enriched ex vivo with mitochondria isolated from healthy donor sources (e.g. allogeneic placenta). The augmented autologous HSPCs are then reinfused into the recipient patient. The first clinical utilization of mitochondrial augmentation was in Pearson Syndrome, a disease caused by a mitochondrial DNA deletion resulting in sideroblastic anemia. To date, 12 Pearson Syndrome patients have been treated with mitochondrial augmentation technology with promising preliminary safety and efficacy. We therefore set out to evaluate the feasibility of this approach in preclinical models of MDS and a phase I trial in adults with spontaneously occurring refractory low-risk MDS. We evaluated the impact of mitochondrial augmentation in a mouse model of MDS driven by the NUP98-HOXD13 (NHD13) fusion. NHD13 mice on a C57BL/6J background develop age-dependent pancytopenia, myelodysplasia, and transformation to AML. We found that long-term HSCs (lineage- cKit+ Sca1+ CD150+ CD48-) from one-year-old NHD13 mice have an aberrant increase in mitochondrial mass, mitochondrial membrane potential, and mitophagy. We then harvested lineage-negative HSPCs from two cohorts of middle-aged NHD13 mice (4 and 7 months) along with littermate controls and performed mitochondrial augmentation using placenta-derived mitochondria from healthy mice of a distinct strain (NZB mice). 200,000 donor HSPCs from CD45.2+ NHD13 or control mice that were either unprocessed or underwent augmentation were infused into irradiated CD45.1+ C57BL/6J recipient mice (10 mice/group/cohort). Across both age cohorts, animals which received augmented NHD13 HSPCs had significantly improved overall survival by a median of 76 days (p<.0001) and 72 days (p<.01) (using 4- and 7-month-old donors respectively) and reduced frequency of AML transformation. Importantly, blood counts were not affected by mitochondrial augmentation in wild-type control HSPCs. We next augmented bone marrow cells isolated from low-risk (LR) MDS patients with exogenous allogeneic placenta-derived mitochondria or a negative control. Mitochondrial augmentation increased erythroid differentiation in all five LR MDS patient samples based on culturing HSPCs in Stemspan medium with erythroid promoting cytokines (a 2-fold mean increase in cell number ± 0.8, p=0.02, one sample Wilcoxon test). Immunophenotypic assessment confirmed increased absolute numbers of mature erythroid cells (CD71+/CD235a+) in the augmented group. Following the above studies, we initiated a phase I clinical trial of mitochondrial augmentation in adults with transfusion-dependent LR MDS refractory to approved therapies (NCT06465160). In this study, autologous mobilized CD34+ cells from LR MDS patients are enriched with allogeneic placenta-derived mitochondria (a product termed MNV-201). Five patients treated to date (median follow up 180 days) demonstrated a high safety profile with no anti-mitochondrial antibodies and no drug-product related adverse events. One patient experienced transfusion independence sustained for 10 months and ongoing. This was a 69-year-old with transfusion-dependent MDS-LB (MDS with low blasts) refractory to erythropoiesis stimulating agents and luspatercept. The patient, transfusion dependent for 7 months prior to enrollment, achieved transfusion independence two months following MNV-201 treatment. The patient also demonstrated improvement in blood-based biomarkers such as GDF-15. Ex vivo erythroid differentiation assays using patient-derived HSPCs revealed significantly increased number and frequency of immature and mature erythroid cells post-augmentation. Collectively, the accumulated mouse and human MDS studies suggest the potential for mitochondrial augmentation of HSPCs to improve the differentiation defect of a subset of human MDS and postpone transformation to acute leukemia. These results support further evaluation of mitochondrial augmentation of HSPCs as a novel autologous cell therapy approach to treat MDS patients.