Targeting Enzymatic Regulation of Fetal Hemoglobin Repression

总体摘要： 这项研究计划的最终目标是提供安全，有效，可及和持久的疾病 镰状细胞性贫血（SCD）的改良，将改善多器官病理生理学和减少早期死亡。 研究支持胎儿血红蛋白是镰状细胞最强有力的天然抑制剂的前提 疾病的病理生理学，以及灭活胎儿γ-珠蛋白（HBG）基因抑制将是治疗， 人类病人本提案的目标侧重于操纵和具体针对 在发育过程中抑制HBG基因的转录调节机制。这些研究 致力于鉴定新的药物靶点，表观遗传酶成分，包括 阻遏机制，这将导致成人红细胞中正常沉默的HBG基因中的γ-珠蛋白激活 祖细胞（项目1），以安全、有效和精致的建模、合成和开发 将在镰状细胞病模型小鼠中进行体外和体内验证的特异性治疗化合物 （项目1和3），对于那些被证明是最有效的线索，继续进行详细的表征， 人类血红蛋白病的最佳模型，狒狒（项目2），为人类临床 试验（项目3）。对患有β-球蛋白病的患者的预计影响是这些提出的HbF-1c水平。 诱导疗法将足够强大，以对抗这些疾病的毁灭性并发症， （中风、急性胸部综合症和早死），并提供安全参数， 作为终身使用。

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.