Mitochondrial dysfunction is often associated with MDS. Studies have shown mitochondrial DNA
(mtDNA) mutations in different MDS subtypes; however, their role in the pathogenesis and
disease progression are not yet clear. Point mutations were found in various locations in the
mitochondrial genome including tRNAs, rRNAs, and mitochondrial proteins.
Mitochondrial fragmentation in hematopoietic stem and progenitor cells (HSPC) can lead to
ineffective hematopoiesis in MDS, suggesting mitochondria as a therapeutic target for
treating MDS.
Mitochondria augmentation therapy (MAT) is a novel cell technology where hematopoietic stem
and progenitor cells (HSPCs) are augmented ex vivo with mitochondria obtained from donor
cells or tissue. MAT is based on the demonstrated ability of isolated mitochondria to enter
cells and impact mitochondrial function and metabolic activity in the recipient cells. The
transfer of mitochondria from cell to cell has been demonstrated using extracellular
vesicles, nanotubes, and micropinocytosis. Mitochondria entering cells provide copies of
normal mtDNA, which can be further propagated via replication within the recipient cell and
via intercellular transfer.
Research will include in vitro and in vivo studies with the bone marrow sample, including,
among other, the following: mitochondrial augmentation of bone marrow aspiration and/or
subpopulations of cells (e.g. CD34+) isolated from the bone marrow aspiration;
differentiation of augmented and/or non-augmented bone marrow aspiration and/or
subpopulations of cells into hematopoietic lineages (e.g. erythroid, megakaryocyte, etc);
assays of mitochondrial content and function; assays of hematopoietic lineages; culture of
augmented and/or non-augmented bone marrow aspiration and/or subpopulations; cryopreservation
of augmented and/or non-augmented bone marrow aspiration and/or subpopulations; sequencing of
mitochondrial DNA and nuclear DNA; in vivo studies of engraftment, biodistribution and
function of augmented and/or non-augmented bone marrow aspiration and/or subpopulations of
cells isolated from the bone marrow aspiration.
Research will include in vitro studies with the peripheral blood sample, including, among
other, the following: immunophenotyping of peripheral blood cells and immune-related
functional assays; mitochondrial content and function of peripheral blood cells.