A small molecule integrin activator to enhance cord blood transplant

DESCRIPTION provided by applicant This proposal is in response to PA the parent announcement for STTR R grant applications Hematopoietic stem cell transplantation has become a preferred treatment for hematological malignancies and certain genetic disorders The use of umbilical cord blood cells as a source of hematopoietic stem cells for bone marrow transplantation has increased steadily over the last decade Due to a less stringent HLA match requirement cord blood transplant has allowed patients to be treated that otherwise could not find a suitable donor Unfortunately there are fewer stem cells in these preparations which results in delayed rates of immunological reconstitution This can lead to a higher incidence of opportunistic infections which increases the rate of graft failures and transplant related mortalities Finding a means to improve the rate of immune reconstitution with cord blood transplants would translate to improved outcomes as well as broader applicability to adult patients Efforts to improve the rate of engraftment of cord blood cells include targeting the cell adhesion cascade which mediates cell homing extravasation and retention in the bone marrow This process is coordinated through the function of chemokines as well as the selectin and integrin families of cell adhesion molecules Promising results have been generated by treating the cells ex vivo to improve the function of the selectin and chemokine mediated processes A drawback to these preconditioning steps is they require additional time expertise and expense As yet the integrins have not been targeted due to a lack of suitable reagents We have developed a unique small molecule that can activate integrins on cord blood cells facilitating their interaction with their counter receptors in the bone marrow This compound can enhance all phases of the adhesion cascade including cell rolling firm adhesion and migration It binds to the integrin directly and activation takes place instantaneously As a result no extensive preconditioning of the cells is necessary This proposal outlines proof of concept studies to evaluate the compound in xenogeneic animal models to determine its effect on cord blood cell homing and engraftment in the bone marrow following transplant PUBLIC HEALTH RELEVANCE The growing use of umbilical cord blood cells for bone marrow transplantation has allowed patients to be treated that otherwise could not find a suitable donor Finding a means to improve the rate of immune reconstitution is critical to fully realize the potential of cord blood transplant and expanding its use to adult patients The studies proposed describe the use of a small molecule cell adhesion activator to facilitate the engraftment rate of cord blood cells and thus decrease the time to immune reconstitution