A non-myeloablative conditioning regimen for hematopoietic stem cell transplantat

造血干细胞移植的非清髓性预处理方案

• 批准号: 8644968
• 负责人: HARTMUT GEIGER
• 金额: $ 36.67万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-17 至 2015-04-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644968
• 关键词: AMD3100; Actins; Adhesions; Adult; Affect; Animals; Antibodies; Antibody Therapy; Autologous; Blood; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; CXCR4 Receptors; Cell Count; Cell Maintenance; Cell Survival; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Chimerism; Clinical; Cytoskeleton; Data; Defect; Disease; Engraftment; Excision; FDA approved; Foundations; Future; Genetic; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immigration; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Integrins; Knowledge; Lead; Left; Mediating; Methods; Morbidity - disease rate; Mus; Non-Malignant; Outcome; Pancytopenia; Patients; Pharmaceutical Preparations; Phase; Physiological; Play; Pre-Clinical Model; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Regimen; Regulation; Role; Signal Transduction; Signaling Molecule; Site; Small Business Innovation Research Grant; Stem cells; Stimulus; Stress; Structural Models; Structure; Testing; Toxic effect; Toxicity Tests; Transducers; Translating; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Validation; Work; adhesion receptor; base; biochemical model; chemokine; chemokine receptor; commercialization; conditioning; design; gene therapy; improved; inhibitor/antagonist; innovative technologies; irradiation; leukemia; migration; mortality; mouse model; novel; novel therapeutics; phase 2 study; pre-clinical; public health relevance; research study; rho GTP-Binding Proteins; small molecule; standard care; stem

Abstract Hematopoietic stem cell transplantation (HSCT) has become a standard care for the treatment of many hematologic malignancies and non-malignant diseases such as bone marrow failure and immunodeficiency syndromes. Currently, myeloablative or irradiative conditioning regimens are used for enhancing HSC engraftment in transplantation, but they are often associated with significant morbidity and mortality, particularly in patients under severe clinical or pathological stress. In addition, in many clinical cases only limited numbers of HSCs are available for transplant. Improving efficiency of BM niche access will improve HSCT outcomes by increasing donor chimerism in clinical settings where stem cell numbers are limiting and recipients are fragile, e.g. in cord blood or gene therapy transplants. As an important intracellular signal transducer of multiple cell stimuli required for HSC maintenance, including signaling from receptor tyrosine kinase c-Kit, chemokine receptor CXCR4 and adhesion receptor integrins, the Rho GTPase Cdc42 plays crucial roles in regulating cell actin cytoskeleton, integrin-mediated adhesion, and chemokine induced directional migration. Structure- function information of Cdc42 derived by structural, biochemical, and mouse model studies have paved the way for the design, identification, and validation of Cdc42-specific inhibitors for translational applications. This Phase I SBIR focuses on developing a novel therapeutic regimen by utilizing CASIN, the Cdc42-targeting small molecule, for opening BM niches to allow donor HSC engraftment, and establishing that Cdc42 targeting can be applied to enhancing human hematopoietic stem cell engraft efficiency in preclinical mouse models without myeloablation or irradiation. Such a conditioning regimen will have immediate commercial value in autologous or human cord blood transplantation therapy where the HSC number is often limited and a significant increase in engraftment will have significant clinical impact. Should the proposed work prove successful, future studies will further develop CASIN and its derivatives in large animal PK/PD and toxicity tests and move for commercialization of this highly promising and innovative technology.

摘要 造血干细胞移植(HSCT)已成为治疗慢性粒细胞白血病的标准护理。 许多恶性血液病和非恶性疾病，如骨髓衰竭和 免疫缺陷综合症。目前，使用清髓性或辐射调理疗法。 用于增强移植中的HSC植入，但它们往往与显著的 发病率和死亡率，特别是在严重的临床或病理压力下的患者。此外, 在许多临床病例中，仅有数量有限的造血干细胞可用于移植。提高效率 通过在临床环境中增加供者嵌合体，骨髓利基获得将改善HSCT结果 干细胞数量有限而受者脆弱的地方，例如脐带血或基因疗法 移植。作为HSC所需的多种细胞刺激的重要细胞内信号转导 维持，包括受体酪氨酸激酶c-Kit，趋化因子受体CXCR4和 黏附受体整合素，Rho GTP酶CDc42在调节细胞肌动蛋白中起重要作用 细胞骨架、整合素介导的黏附和趋化因子诱导定向迁移。结构- 通过结构、生化和小鼠模型研究得出的cdc42的功能信息 为设计、鉴定和验证cdc42特定的翻译抑制剂铺平了道路。 申请。这一阶段的SBIR专注于开发一种新的治疗方案，通过使用 Casin是一种以CdC42为靶向的小分子，用于打开BM利基以允许捐赠者HSC植入， 并确定了CDC42靶向可以应用于增强人的造血干细胞 未经清髓或照射的临床前小鼠模型中的移植效率。这样的一个 调理方案在自体或人类脐带血中将立即具有商业价值 移植治疗的情况下，造血干细胞的数量往往是有限的，并显著增加 植入物将对临床产生重大影响。如果提议的工作被证明是成功的，未来 研究将进一步开发酪蛋白及其衍生物在大型动物PK/PD中的应用和毒性试验 推动这项极具前景的创新技术的商业化。