Enhanced Engraftment with Fucosylation of Cord Blood and Mesenchymal Stem Cells
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AbstractDESCRIPTION (provided by applicant): Three primary sources of hematopoietic stem cells (HSCs) are routinely used in HSC therapy. These include mobilized peripheral blood, bone marrow and umbilical cord. While each source has its individual benefits, cord blood has seen increased usage over the past decade due to its availability from numerous cord blood banks, along with a reduced risk of GVHD. However, the slow rate of engraftment and leukocyte re- population of peripheral blood compared with that for stemcells from other sources severely limits the utilization of this rich source of HSCs and accounts, in part, for a high infection rate and patient mortality. Studies to date suggest that delayed engraftment following injection of cord blood (CB) is due primarily to reduced homing of these stem cells to the bone marrow. Furthermore, recent attention has focused on the damage to the bone marrow following myeloablation and the benefits of co-administering hematopoietic stem cells with mesenchymal stem cells (MSCs) to improve recovery rate. The deficit in homing of CB-derived stem cells can be overcome with the pretreatment of these cells with America Stem Cell's (ASC's) proprietary technology (ASC101). Application of this technology involves ex vivo enzymatically mediated fucosylation of specific cell surface glycoproteins prior to transplant. In particular, when human CB was subjected to pre- incubation with ASC101 which is composed of fucosyltransferase VI and its substrate (GDP-fucose), an increased rate ofengraftment was observed in a small animal xenotransplant model. More recently, it was shown that enforced fucosylation of MSCs also enhances the homing of this stem cell population to the bone marrow. The goal of the proposed Phase I SBIR project is to identify the therapeutic potential for ex vivo fucosylation of CB HSCs and MSCs with regard to enhanced rate and extent of hematopoietic recovery. To prove the feasibility of this novel approach, the ASC research team will profile hematopoietic reconstitution with the co-administration of these cells, following ex vivo fucosylation. We will initially establish the concentration of fucosylated MSCs needed to enhance CB HSC engraftment (Aim #1). We will then optimize the time interval for administration of both cells types (Aim #2). Finally, we propose to explore the effect of administration of ex vivo fucosylated CB HSCs + fucosylated MSCs on the rate and extent of hematopoietic recovery (Aim# 3) following co-administration along with a secondary transplant study to indentify the contribution of long-term repopulating stem cells to recovery.
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