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（由申请人提供）：该提案是对 STTR (R41) 拨款申请的母公司公告的回应，造血干细胞移植已成为血液恶性肿瘤和某些遗传性疾病的首选治疗方法。脐带血细胞作为骨髓移植的造血干细胞来源在过去十年中稳步增加，由于 HLA 匹配要求不太严格，脐带血移植已成为可能。不幸的是，这些制剂中的干细胞较少，导致免疫重建速度延迟，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寻找一种提高脐带血移植免疫重建率的方法将转化为改善的结果以及更广泛的适用性，以提高脐带血细胞的植入率，包括针对细胞。 介导细胞归巢、外渗和保留在骨髓中的粘附级联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，通过离体处理细胞已产生了有希望的结果。改善选择素和趋化因子介导过程的功能，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，但由于整合素尚未被靶向。我们开发了一种独特的小分子，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。这种化合物可以增强粘附级联的所有阶段，包括细胞滚动、牢固。它直接与整合素结合并立即发生激活，因此不需要对细胞进行广泛的预处理来评估该化合物。在异种动物模型中确定其对移植后脐带血细胞归巢和植入骨髓的影响。