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.
