A small molecule integrin activator to enhance cord blood transplant

 描述（由申请人提供）：本提案是对PA-15-270的回应，这是STTR（R41）赠款申请的母公司公告。造血干细胞移植已成为血液系统恶性肿瘤和某些遗传性疾病的首选治疗方法。在过去的十年中，使用脐带血细胞作为骨髓移植的造血干细胞来源稳步增加。由于HLA匹配要求不那么严格，脐带血移植允许患者接受治疗，否则无法找到合适的供体。不幸的是，这些制剂中的干细胞较少，这导致免疫重建速率延迟。这可能导致机会性感染的发生率更高，从而增加移植失败率和移植相关死亡率。找到一种方法来提高脐带血移植的免疫重建率将转化为改善的结果以及更广泛的适用于成人患者。提高脐带血细胞植入率的努力包括靶向细胞 粘附级联介导骨髓中的细胞归巢、外渗和滞留。这一过程通过趋化因子以及细胞粘附分子的选择素和整合素家族的功能来协调。通过离体处理细胞以改善选择素和趋化因子介导的过程的功能已经产生了有希望的结果。这些预处理步骤的缺点是它们需要额外的时间、专业知识和费用。到目前为止，由于缺乏合适的试剂，整联蛋白尚未被靶向。我们已经开发出一种独特的小分子，可以激活脐带血细胞上的整合素，促进它们与骨髓中的反受体相互作用。该化合物可以增强粘附级联的所有阶段，包括细胞滚动、牢固粘附和迁移。它直接与整联蛋白结合，并立即激活。因此，不需要对细胞进行广泛的预处理。该提案概述了概念验证研究，以评估异种动物模型中的化合物，以确定其对移植后脐带血细胞归巢和骨髓植入的影响。

 DESCRIPTION (provided by applicant): This proposal is in response to PA-15-270, the parent announcement for STTR (R41) 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.