Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

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Science Translational Medicine  08 Feb 2017:
Vol. 9, Issue 376, eaah5645
DOI: 10.1126/scitranslmed.aah5645

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Inducing autophagy to improve anemia

Diamond-Blackfan anemia (DBA) is a rare blood disorder characterized by insufficient red blood cell production that is treated with corticosteroids and transfusion therapy. To identify additional therapeutics for DBA, Doulatov et al. performed a chemical screen with hematopoietic progenitor cells derived from iPSCs from two DBA patients with RPS19 and RPL5 genetic mutations. The autophagy inducing small-molecule SMER28 rescued erythroid differentiation in an autophagy factor ATG5-dependent manner in iPSC-derived patient cells, in zebrafish models of DBA, and in several mouse models. These results demonstrate the utility of iPSC-based screens for drug discovery for rare blood disorders and identify SMER28 and the autophagy pathway as promising targets for DBA therapy.


Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.

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