Ex Vivo Fucosylation of Cord Blood with FTVII and Enhanced Hematopoietic Recovery
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AbstractDESCRIPTION (provided by applicant): The three primary sources of hematopoietic stem cells (HSCs) for bone marrow transplant are: mobilized peripheral blood, bone marrow, and umbilical cord. While each source has its individual benefits and limitations, cord blood has seen increased usage over the past decade due to its ready availability from numerous cord blood banks in the US, along with a reduced risk of GVHD and greater tolerance for the number of MHC mismatches. However, the slow rate of engraftment and hematopoietic recovery, compared with that seen for stem cells from the other sources, severely limits the utilization of this rich source of hematopoietic stem cells 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 the stem cells to the bone marrow. America Stem Cell (ASC) has shown that this deficit in homing can be overcome following the ex vivo pretreatment of CB with our proprietary technology (ASC101). This technology accomplishes ex vivo enzymatically-mediated fucosylation of subunits on cell surface selectin glycoprotein ligands, such as PSGL, E-selectin, CD44. In particular, when human CB was subjected to pre-incubation with ASC101 (fucosyltransferase VI and its substrate, GDP-fucose), this resulted in an increased rate and extent of engraftment following injection of the ASC101-pretreated CD34+ cells in a small animal bone marrow transplant model. We now present exciting new data showing that selectin-mediated binding is significantly improved following enforced fucosylation with the endogenous enzyme, FTVII, over that seen using FTVI. This has important implications for enhancing in vivo homing andhematopoietic recovery by using FTVII in the ASC101 reagent mix . These findings have the potential to open up a new area in our understanding of the glycobiology of cell engraftment, with potentially important implications for the use of fucosylation in cell therapy. The goal of the presently proposed Phase I SBIR is to explore the enhanced therapeutic potential following ex vivo fucosylation of CB HSCs using FTVII vs. FTVI. To extend on the present positive preliminary in vitro data with FTVII, we will comparatively assess the rate and extent of hematopoietic reconstitution following ex vivo fucosylation with FTVII vs. FTVI. We will first identify the limiting (ED50) dose of untreated, injected CD34+ needed to achieve engraftment in a cell dose response study using NOD/SCID gamma null mice (Aim #1). We will use this identified dose of injected CD34+ cells to comparatively assess the effect of ex vivo incubation with FTVII vs. FTVI on the rate and extent of hematopoietic recovery (Aim #2). PUBLIC HEALTH RELEVANCE: Many bone marrow transplant candidates do not have access to potential grafts that can provide the degree of donor/host match required to avoid rejection or complications mediated by immune reactions. Fortunately, cord blood (CB) is a well recognized alternative source of hematopoietic stem cells that can be utilized with a lower rate of infections and rejection. However, a significant challenge to the widespread use of cord blood is the documented reduced ability of these stem cells to migrate to the bone marrow following systemic administration. America Stem Cell (ASC) has shown in preclinical studies that it can enhance the homing and engraftment of CB stem cells following ex vivo enforced fucosylation with its proprietary technology (ASC101) using FTVI. We now show in preliminary studies that we can significantly increase selectin-mediated binding and the potential for enhanced homing following enforced fucosylation using the endogenous enzyme, FTVII. The present studies will set the stagefor successful development and commercialization of a next-generation technology that will greatly improve patient outcomes, quality of life and potentially reduce healthcare costs.
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