Session: 701. Experimental Transplantation: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Acquired Marrow Failure Syndromes, Translational Research, Bone Marrow Failure Syndromes, Inherited Marrow Failure Syndromes, Diseases, Myeloid Malignancies, Technology and Procedures
We therefore sought here to evaluate a similar mitochondrial augmentation cell therapy approach in spontaneous adult MDS. We hypothesized that enrichment of MDS patient-derived cells with healthy, functional mitochondria may improve HSPC functionality and rescue ineffective hematopoiesis. We subjected bone marrow cells from low-risk (LR) MDS patients to augmentation with exogenous allogeneic mitochondria from healthy term placenta or a negative control. Mitochondrial augmentation increased erythroid differentiation capacity 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 with mitochondrial augmentation was seen, p=0.02, one sample Wilcoxon test). Immunophenotypic assessment confirmed increased absolute numbers of mature erythroid cells (CD71+/Ter119+) in the augmented group.
Xenotransplantation of patient MDS cells into immunocompromised mice has been a historical challenge. Out of six bone marrow derived LR MDS patient samples, five showed engraftment (defined as >1% human CD45+ cells) ~17 weeks post-transplantation into unirradiated NBSGW mice. Interestingly, intravenous infusion of mitochondrially augmented bone marrow derived cells from LR MDS patients resulted in greater (1.6-5.3-fold increase) engraftment in bone marrow relative to non-augmented samples with multilineage (myeloid and B- and T- lymphoid) reconstitution in two of five patients. Studies to determine the impact of mitochondrial augmentation on clonality based on MDS-associated somatic mutations did not demonstrate alterations in variant allele frequency after in vitro or in vivo studies, and no increase in AML-related mutations was observed.
To further assess the impact of mitochondrial augmentation on MDS therapeutic differentiation and transformation potential in vivo, we utilized lineage negative HSPCs from the NUP98-HOXD13 (NHD13) mouse model of MDS. Irradiated C57BL mice received an infusion of 200,000 HSPCs from aged (6-month-old) wild-type C57BL mice or NHD13 mice that were either unprocessed or mitochondrially augmented with placenta-derived mitochondria from healthy mice of a distinct strain (NZB mice). Within 35 days, all ten animals which received non-augmented NHD13 cells were dead or moribund due to AML development, whereas all animals which received augmented NHD13 HSPCs survived with a median of 114 days (p<.0001, log-rank test). Importantly, blood counts were not affected by mitochondrial augmentation in wild-type control bone marrow.
Taken together, the accumulated studies with mouse and human MDS models suggest the potential for mitochondrial augmentation of HSPCs to improve the differentiation defect of a subset of human MDS, enhance in vivo reconstitution potential, and postpone transformation to acute leukemia. These preclinical results support the potential of mitochondrial augmentation of HSPCs as a novel approach to treat MDS patients utilizing autologous cell therapy.
Disclosures: Avni: Minovia Therapeutics: Current Employment. Kutner: Minovia Therapeutics: Current Employment. Khoury: Minovia Therapeutics: Current Employment. Pozner: Minovia Therapeutics: Current Employment. Sabath: Minovia Therapeutics: Current Employment. Ziv: Minovia Therapeutics: Current Employment. Ofran: Minovia Therapeutics: Membership on an entity's Board of Directors or advisory committees. Napso: Minovia Therapeutics: Current Employment. Yivgi Ohana: Minovia Therapeutics: Current Employment. Sher: Minovia Therapeutics: Current Employment. Abdel-Wahab: Minovia Therapeutics: Consultancy, Research Funding; Nurix Therapeutics: Research Funding; Codify Therapeutics: Consultancy, Current equity holder in private company, Research Funding.
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