A non-myeloablative conditioning regimen for hematopoietic stem cell transplantat

摘要 造血干细胞移植（HSCT）已成为治疗造血干细胞缺乏症的标准护理。 许多血液恶性肿瘤和非恶性疾病如骨髓衰竭， 免疫缺陷综合征目前，使用清髓性或放射性预处理方案 用于增强移植中HSC的植入，但它们通常与显著的 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中。此外，本发明还提供了一种方法， 在许多临床病例中，只有有限数量的HSC可用于移植。提高效率 骨髓小生境进入将通过增加临床环境中的供体嵌合体来改善HSCT结局 在干细胞数量有限且受体脆弱的情况下，例如在脐带血或基因治疗中 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CXCR 4和 粘附受体整合素，Rho GTs Cdc 42在调节细胞肌动蛋白 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获得的Cdc 42的功能信息， 为Cdc 42特异性抑制剂的设计、鉴定和验证铺平了道路。 应用.该I期SBIR的重点是开发一种新的治疗方案， 卡辛，Cdc 42靶向小分子，用于打开BM龛以允许供体HSC植入， 并确定Cdc 42靶向可用于增强人造血干细胞 在没有骨髓消融或辐射的临床前小鼠模型中的移植效率。这样的 预处理方案将在自体或人脐带血中具有直接的商业价值 HSC数量通常有限的移植治疗， 移植将具有显著的临床影响。如果计划成功，未来 研究将进一步开发卡辛及其衍生物在大型动物PK/PD和毒性试验中的应用， 推动这一极具前景和创新技术的商业化。

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.