Overall Abstract: The ultimate goal of this research program is to provide safe, effective, accessible and durable disease modification for sickle cell anemia (SCD) that will improve multi-organ pathophysiology and reduce early death. Research studies support the premise that fetal hemoglobin is the most powerful natural inhibitor of sickle cell disease pathophysiology, and that inactivating fetal γ-globin (HBG) gene repression would be therapeutic in human patients. The goals of this proposal focus on the manipulation and specific targeting of the transcriptional regulatory machinery that represses HBG genes during development. These studies are devoted to the identification of new drug targets, the epigenetic enzyme components that comprise the repression machinery, that will lead to γ-globin activation in the normally silenced HBG genes in adult erythroid progenitor cells (Project 1), to the modeling, synthesis and development of safe, effective and exquisitely specific therapeutic compounds that will be validated in vitro and in vivo in sickle cell disease model mice (Projects 1 and 3), and for those leads that prove to be most efficacious, onward to detailed characterization in the optimal model for human hemoglobinopathies, the baboon (Project 2) in preparation for human clinical trials (Project 3). The projected impact for patients suffering from β-globinopathies is that these proposed HbF- inducing therapies will be sufficiently robust so as to counter the devastating complications of these diseases (stroke, acute chest syndrome and early death) with safety parameters that will permit universal access as well as life-long use.