Strategies for Prenatal Stem Cell Tranplantation

描述：(研究人员摘要)宫内造血干细胞移植(IUHSCTx)是一种很有前途的治疗方法。 各种先天性血液病的病因。然而，在没有 对正常细胞、临床和实验工作的选择优势 IUHSCTx导致有限的或没有可检测到的植入物，支持 造血竞争性移植中存在的主要植入障碍 收件人。该项目的长期目标是开发临床应用 将植入率提高到治疗性水平的适用策略。克服困难 植入障碍将增加IUHSCTx的临床应用 具有降低发病率、死亡率和成本的潜力， 目前可用的治疗方法。这项建议的具体目的是：1. 优化供者细胞亚群用于宫内造血干细胞移植 移植。归宿、寄存和植入的要求 人们对胎儿肝脏知之甚少。捐赠者细胞群在他们的 嫁接效率。使用新的策略，特定的捐赠者细胞群体 将比较它们的早期植入动力学，相对 移植细胞的再生能力和移植后的竞争能力 等量更新种群的IUHSCTx。这将为我们提供对 IUHSCTx和UHSCTx后特定供者群体移植的相对能力 初始移植的HSC数量与移植的 捐助者群体的竞争能力，以实现高水平 2.研究以免疫为基础的策略对 加强产前植入，提高嵌合体水平 出生后。这一具体目标有三个目标：1)识别和验证 植入无移植物抗宿主病(GVHD)的浓缩HSC；2)至 研究产前免疫治疗策略以抑制GVHD并改善 IUHSCTx后非浓缩供者群体的植入；以及3)测试 出生后免疫治疗方法减少或消除的效果 IUHSCTx耐受的混合嵌合受体的宿主造血功能 本提案中的研究旨在确定和测试战略，以 增加IUHSCTx术后植入率。这将允许应用此 研究范围广泛的产前诊断的遗传性疾病。

DESCRIPTION: (Investigator's abstract) In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising therapeutic approach for the treatment of a variety of congenital hematologic disorders. However, in the absence of a selective advantage for normal cells, clinical and experimental efforts at IUHSCTx have resulted in limited or no detectable engraftment, supporting the existence of major barriers to engraftment in the hematopoietically competitive recipient. The long-term objective of this project is to develop clinically applicable strategies to increase engraftment to therapeutic levels. Overcoming the engraftment barrier would allow increased clinical application of IUHSCTx with the potential for reduced morbidity, mortality, and cost, relative to currently available therapy. The specific aims of this proposal are: 1. To optimize donor cell subpopulations for engraftment after in utero HSC transplantation. The requirements for homing, lodgement and engraftment to the fetal liver are poorly understood. Donor cell populations differ in their engraftment efficiency. Using novel strategies, specific donor cell populations will be compared for their early kinetics of engraftment, the relative repopulating ability of engrafted cells, and the competitive capacity after IUHSCTx of equivalent repopulating populations. This will provide insight into the relative ability of specific donor populations to engraft after IUHSCTx and into the relative importance of initial number of HSC engrafted, versus the competitive capacity of the donor population, for the achievement of high level engrafment. 2. To investigate the efficacy of immune based strategies to enhance engraftment prenatally, and to increase levels of chimerism postnatally. This Specific Aim has three goals: 1) To identify and validate specific donor derived cell populations that can facilitate prenatal engraftment of enriched HSC without graft versus host disease (GVHD); 2) to investigate prenatal immunotherapeutic strategies to suppress GVHD and improve engraftment of non-enriched donor populations after IUHSCTx; and 3) to test the efficacy of immunotherapeutic approaches after birth to reduce or eliminate host hematopoiesis in the mixed chimeric recipient made tolerant by IUHSCTx. The studies in this proposal are designed to identify and test strategies to increase engraftment after IUHSCTx. This would allow application of this approach to a broad range of prenatally diagnosed genetic disorders.