Stem cells for therapeutics discovery in genetic blood disorders

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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.