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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的造血干细胞移植（HSCT）已成为治疗以下疾病的标准护理许多血液恶性肿瘤和非恶性疾病，例如骨髓衰竭和免疫缺陷综合症。目前，使用清髓或放射调理方案用于增强移植中 HSC 的植入，但它们通常与显着相关发病率和死亡率，特别是在严重临床或病理应激下的患者中。此外，在许多临床病例中，只有有限数量的造血干细胞可用于移植。提高效率 BM 利基访问将通过增加临床环境中的供体嵌合来改善 HSCT 的结果干细胞数量有限且受体脆弱的地方，例如脐带血或基因治疗移植。作为 HSC 所需的多种细胞刺激的重要细胞内信号转导器维持，包括来自受体酪氨酸激酶 c-Kit、趋化因子受体 CXCR4 和粘附受体整合素，Rho GTPase Cdc42 在调节细胞肌动蛋白中起着至关重要的作用细胞骨架、整合素介导的粘附和趋化因子诱导的定向迁移。结构- 通过结构、生化和小鼠模型研究得出的 Cdc42 功能信息为 Cdc42 特异性转化抑制剂的设计、鉴定和验证铺平了道路应用程序。该 I 期 SBIR 重点是利用 CASIN，Cdc42 靶向小分子，用于打开 BM 生态位以允许供体 HSC 植入，并确定Cdc42靶向可用于增强人类造血干细胞无需清髓或照射的临床前小鼠模型的移植效率。这样一个调理方案将在自体或人类脐带血中具有直接的商业价值移植治疗中 HSC 数量通常有限，并且 HSC 数量显着增加移植将产生重大的临床影响。如果拟议的工作被证明成功，未来研究将进一步开发CASIN及其衍生物在大动物PK/PD和毒性试验中的应用推动这项极具前景的创新技术的商业化。