A small molecule integrin activator to enhance cord blood transplant

增强脐带血移植的小分子整合素激活剂

• 批准号: 9139272
• 负责人: Upendra Marathi
• 金额: $ 29.59万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139272
• 关键词: Adhesions; Adult; Agonist; Allogenic; Animal Model; Applications Grants; Binding; Biological Assay; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Brain; C57BL/6 Mouse; Cell Adhesion; Cell Adhesion Molecules; Cell Transplants; Cells; Chemicals; Childhood; Clinical Trials; Collecting Cell; Data; Development Plans; Disadvantaged; Dose; Drug Kinetics; Endothelium; Engraftment; Event; Extravasation; Family; Female; Flow Cytometry; Future; Heart; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematoxylin and Eosin Staining Method; Hereditary Disease; Homing; Human; Immune; Incidence; Inflammatory Infiltrate; Injection of therapeutic agent; Institutes; Integrin alpha4beta1; Integrins; Investigational New Drug Application; Kidney; Lead; Leukocyte Trafficking; Licensing; Ligands; Liver; Lung; Mediating; Methods; Modeling; Mus; Opportunistic Infections; PTPRC gene; Parents; Patients; Phase; Pilot Projects; Plasma; Population; Preparation; Process; Production; Prostaglandins I; Protease Inhibitor; Quality Control; Reagent; Reporting; Risk; Role; Route; Safety; Schedule; Selectins; Series; Siblings; Small Business Technology Transfer Research; Source; Spleen; Staging; Staining method; Stains; Stem cells; Stromal Cell-Derived Factor 1; Surface; Testing; Texas; Time; Tissues; Translating; Transplantation; Umbilical Cord Blood; Vascular Cell Adhesion Molecule-1; Work; analog; analytical method; chemokine; graft failure; graft vs host disease; hematopoietic tissue; human cord blood CD34+ cell; improved; improved functioning; improved outcome; in vivo; male; method development; migration; mortality; nonhuman primate; peripheral blood; phase 2 study; preconditioning; public health relevance; receptor; reconstitution; response; safety study; small molecule; stem

 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.

 描述（由应用程序提供）：此提案是对STTR（R41）赠款申请的父母公告PA-15-270的响应。造血干细胞移植已成为血液系统恶性肿瘤和某些遗传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造血干细胞的来源稳定增加。由于HLA匹配要求不太严格，因此脐带血移植允许对患者进行治疗，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，这导致免疫重建率延迟。这可能导致机会性感染的发生率更高，从而增加了移植失败和移植相关的死亡率的发生率。找到一种通过绳索血液移植提高免疫财产率率的方法，可以转化为改善的结果，并更广泛地适用于成年患者。提高脐带血细胞植入率的努力包括针对细胞 粘附的级联反应介导骨髓中的细胞归巢，渗出和保留率。该过程通过趋化因子的功能以及细胞粘合剂分子的选择素和整合素家族进行协调。通过治疗细胞外体以改善选择素和趋化因子介导的过程的功能来产生有希望的结果。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，整联蛋白尚未针对。我们已经开发了一种独特的小分子，可以激活脐带血细胞上的整联蛋白，从而支持它们与骨髓中的反感应器的相互作用。该化合物可以增强粘合剂级联反应的所有阶段，包括细胞滚动，粘合剂和迁移。它直接与整联蛋白结合，并立即进行激活。结果，不需要对细胞进行广泛的预处理。概述了概念验证研究，以评估异构动物模型中的化合物，以确定其对移植后骨髓中脐带血细胞寄养和植入的影响。