Stem cells for therapeutics discovery in genetic blood disorders

摘要 在祖细胞生物学联盟 (PCBC) 的支持下，我们的中心位于 波士顿儿童医院在斑马鱼和人类身上使用了公正的化学筛选 诱导多能干细胞 (iPS) 鉴定出两种拯救造血功能的药物 钻石黑扇贫血症是一种遗传性骨髓衰竭综合征，缺乏 充分的药物或细胞治疗。在下一阶段的最初几年—— 祖细胞翻译联盟——我们建议启动临床试验 这些代理人，并建立一个综合中心，在随后的几年里 将开发新药、基于祖细胞的细胞疗法和基因疗法 其他遗传性血液疾病，包括Shwachman Diamond Syndrome、Fanconi 贫血、先天性角化不良、原发性免疫缺陷和血红蛋白病。 我们将培养内部发现和临床转化的能力，以及 邀请外部合作的核心设施和通用平台 调查员，从而服务于 PCTC 更广泛的使命。我们目标的成功将 解决基本研究方面大量未满足的需求 遗传性血液病的机制和新疗法的开发 这些疾病虽然个别罕见，但总体而言是血液学的重大挑战。 考虑到分析，血液作为发现系统具有相当大的优势 血统的试剂和分子目录比比皆是；的概率很高 血液疾病的成功将为利用该技术建立强大的原理证明 人类 iPS 细胞模型用于其他疾病的临床转化。

Abstract Under the auspices of the Progenitor Cell Biology Consortium (PCBC), our hub at Boston Children's Hospital used unbiased chemical screens in zebrafish and human induced Pluripotent Stem (iPS) Cells to identify two drugs that rescue the hematopoietic defects in Diamond Blackfan Anemia, a genetic bone marrow failure syndrome that lacks adequate pharmacologic or cell-based treatments. In the initial years of the next phase— the Progenitor Cell Translation Consortium—we propose to initiate clinical trials with these agents, and to establish a comprehensive center that during the subsequent years will develop new drugs, progenitor-based cell therapies, and gene therapies for additional genetic blood diseases, including Shwachman Diamond Syndrome, Fanconi Anemia, Dyskeratosis Congenita, primary immune deficiency, and hemoglobinopathy. We will build competency for both internal discovery and clinical translation, as well as Core facilities and generic platforms that will invite collaborations from external investigators, thereby serving the broader mission of the PCTC. Success in our aims will address considerable unmet needs for both the investigation of fundamental mechanisms of genetic blood disease and the development of novel therapeutics for conditions that while individually rare, are collectively a major challenge for hematology. The blood affords considerable advantages as a discovery system, given that analytic reagents and molecular catalogues of blood lineages abound; the high probability of success for blood diseases will establish a powerful proof-of-principle for leveraging human iPS cell models in clinical translation for other diseases.