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: 9907800
• 负责人: Upendra Marathi
• 金额: $ 93.6万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907800
• 关键词: Adhesions; Adult; Antifungal Agents; Applications Grants; Biodistribution; Biological Assay; Biological Availability; Blood Cells; Blood specimen; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CD34 gene; CYP3A4 gene; Canis familiaris; Cell Adhesion; Cell Adhesion Molecules; Cell Count; Cell Transplantation; Cells; Clinical; Clinical Research; Clinical Trials; Cyclic GMP; Development; Disadvantaged; Dose; Drug Interactions; Drug Kinetics; Engraftment; Enzymes; Extravasation; Family; Food; Formulation; Funding; Future; Genetic Diseases; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Homologous Transplantation; Hospitalization; Incidence; Integrin alpha4beta1; Integrins; Investigational Drugs; Investigational New Drug Application; Ketoconazole; Lead; Leukocytes; Lipids; Liver; Mediating; Modeling; Multiple Myeloma; Mus; NOD/SCID mouse; Opportunistic Infections; Oral; PTPRC gene; Parents; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Procedures; Process; Production; Rattus; Reagent; Regimen; Research Design; Risk; Running; Safety; Schedule; Selectins; Small Business Technology Transfer Research; Source; Stem cell transplant; Subgroup; Technology; Testing; Thyroid Function Tests; Thyroid Hormones; Thyroxine; Time; Toxic effect; Toxicology; Translating; Transplantation; Triiodothyronine; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; United States Food and Drug Administration; adhesion receptor; base; bone cell; capsule; carcinogenicity; chemokine; cost; design; genotoxicity; graft failure; graft vs host disease; human cord blood CD34+ cell; immune reconstitution; improved; improved functioning; improved outcome; infection risk; inhibitor/antagonist; leukemia/lymphoma; liver function; meetings; migration; mortality; new technology; peripheral blood; phase 1 study; pre-clinical; preconditioning; receptor; reconstitution; response; safety study; small molecule; stability testing; stem cells; trafficking; transplant model

PROJECT SUMMARY This proposal is in response to the parent announcement for Phase II STTR (R42) grant applications. Hematopoietic stem cell transplantation has become a preferred treatment for hematological malignancies and certain genetic disorders. Umbilical cord blood has become an appealing alternative to bone marrow or peripheral blood as a source of hematopoietic stem cells for transplant. 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 can be dosed independently of the cells and is inexpensive to synthesize on a large-scale. This would have an advantage over other technologies as no preconditioning or manipulations of the cells would be required meaning a more affordable and universally translatable therapy. We have demonstrated proof-of-concept in our phase I studies that dosing 7HP349 following transplant of human CD34+ cord blood cells into NOD-SCID mice leads to increased engraftment of CD34+ cells in the bone marrow and increased CD45+ cell counts in peripheral blood. Our phase II proposal includes aims to refine the dosing schedule and preclinical formulation and toxicity studies required to file an Investigational New Drug application with the Food and Drug Administration.

项目摘要 该提案是对II阶段STTR（R42）赠款申请的父母公告的回应。 造血干细胞移植已成为血液恶性肿瘤的首选治疗方法 某些遗传疾病。脐带血已成为骨髓或 外周血作为移植的造血干细胞的来源。由于HLA比赛不太严格 要求，脐带血移植已允许治疗患者，否则找不到合适的 捐助者。不幸的是，这些制剂中的干细胞较少，导致延迟的速度 免疫机构。这可能导致机会感染的发病率更高，从而增加 移植失败和与移植相关的死亡率的率。寻找提高免疫速率的手段 用脐带血移植重构将转化为改善的结果，更广泛的适用性 给成人患者。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。这个过程 通过趋化因子的功能以及细胞粘附的selectin和整合素家族进行协调 分子。通过治疗细胞以改善细胞来改善细胞的功能，产生了有希望的结果 选择素和趋化因子介导的过程。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。由于缺乏合适的 试剂。我们已经开发了一个独特的小分子，可以激活脐带血细胞上的整联蛋白， 促进他们与骨髓中的反感应器的相互作用。这种化合物可以增强所有 粘附级联反应的阶段，包括细胞滚动，牢固的粘附和迁移。它可以加入 独立于细胞，并且在大规模上合成。这将有优势 在其他技术中，不需要对细胞进行预处理或操纵，这意味着更多 负担得起且普遍可翻译的疗法。我们已经证明了I阶段研究的概念证明 将人CD34+脐带血细胞移植到点头scID小鼠之后，服用7HP349的给药导致 增加骨髓中CD34+细胞的植入增加，并增加周围的CD45+细胞计数 血。我们的第二阶段提案包括旨在完善剂量时间表和临床前的配方和 向食品药品监督管理局提交研究新药应用所需的毒性研究。