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Stem cells for therapeutics discovery in genetic blood disorders

干细胞用于遗传性血液疾病的治疗发现

基本信息

批准号：
10188598
负责人：
George Q Daley
金额：
$ 122.31万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188598
关键词：
Address Alleles Anemia Biological Assay Blood Boston CRISPR/Cas technology Catalogs Cell Therapy Cell Transplantation Cells Cellular biology Chemicals Clinical Clinical Trials Collaborations Communities Competence Core Facility Data Defect Development Diamond-Blackfan anemia Disease Dyskeratosis Congenita Erythroid Erythropoiesis FDA approved Fanconi&apos s Anemia Fishes Genetic Genetic Models Genetically Engineered Mouse Goals Hematological Disease Hematology Hematopoietic Hematopoietic stem cells Hemoglobinopathies Human Immune In Vitro Individual Inherited Institution Investigation Lead Mission Modeling Molecular Mus Mutagenesis National Heart, Lung, and Blood Institute Other Genetics Pancytopenia Pathology Patients Pediatric Hospitals Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phenotype Pluripotent Stem Cells Population Probability RPS19 gene Reagent Research Personnel Shwachman-Diamond syndrome System Techniques Testing Therapeutic Therapeutic Effect Translations Trifluoperazine Umbilical Cord Blood Work Zebrafish analog base blood lead bone marrow failure syndrome clinical translation disability disease phenotype drug repurposing gene therapy hematopoietic differentiation humanized mouse in vivo induced pluripotent stem cell insight mouse model novel novel strategies novel therapeutics progenitor repaired screening small hairpin RNA small molecule stem stem cell model stem cell therapy stem cells success therapeutic gene treatment strategy

项目摘要

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.

摘要在祖细胞生物学联盟（PCBC）的赞助下，我们在波士顿儿童医院在斑马鱼和人类中使用了无偏见的化学筛选诱导多能干细胞（iPS），以确定两种药物，拯救造血干细胞， Diamond Blackfan贫血是一种遗传性骨髓衰竭综合征，适当的药理学或基于细胞的治疗。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，这些代理商，并建立一个全面的中心，在随后的几年里，将开发新的药物，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综合征，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翻译的能力，以及核心设施和通用平台将邀请外部合作调查员，从而为PCTC更广泛的使命服务。我们的目标若能成功，解决大量未得到满足的需求，遗传性血液病的机制和新疗法的发展，这些疾病虽然个别罕见，但总体上是血液学的主要挑战。血液作为一种发现系统提供了相当大的优势，血液谱系的试剂和分子目录比比皆是; 血液病治疗的成功将为杠杆作用建立一个强有力的原则证明，人类iPS细胞模型在其他疾病的临床转化中的应用。