NOVEL TREATMENT STRATEGIES FOR SICKLE CELL DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 镰状细胞病(SCD)是一种严重的遗传性血液疾病，在美国约有70,000人受到影响，在非洲每年有20多万新生儿出生。对SCD分子发病机制的巨大见解转化为有效的治疗方法进展缓慢。生化、流行病学和临床研究已经确凿地证明，胎儿血红蛋白(HBF)水平的增加抑制了镰状血红蛋白的聚合，显著改善了疾病。美国FDA批准的唯一一种治疗SCD的药物是羟基尿素，只有25%的成年患者从中获得了显著的好处。我们和其他人在体外积累了广泛的证据，表明组蛋白去乙酰化酶(HDAC)抑制剂voinostat可以诱导原代红系细胞中胎儿血红蛋白的表达，因此是进一步临床前开发镰状细胞疾病的极佳候选者。在这个项目中，我们在去血猕猴灵长类动物模型上进行了伏立诺的剂量递增药效学研究，该模型用于确定羟基尿素的疗效。我们将通过定量聚合酶链式反应(定量聚合酶链式反应)、胎儿血红蛋白蛋白水平(用高效液相色谱)、F细胞频率(用流式细胞仪)、珠蛋白乙酰化和红细胞流变学来检测威力诺对珠蛋白基因表达水平的影响。我们将首先用递增剂量的镇涡剂治疗一只动物，随后计划将镇涡剂与羟基尿素联合使用，以评估可能的附加益处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sickle cell disease (SCD) is a severe hereditary blood disease that affects approximately 70,000 individuals in the United States and over 200,000 births per year in Africa. Tremendous insights into the molecular pathogenesis of SCD have been slow to translate to effective therapies. Biochemical, epidemiological, and clinical studies have conclusively demonstrated that increased levels of fetal hemoglobin (HbF) inhibit polymerization of sickle hemoglobin and significantly ameliorate the disease. The only FDA-approved drug in the US for SCD is hydroxyurea, to which only 25% of adult patients derive significant benefit. We and others have accumulated extensive evidence in vitro that vorinostat, a histone deacetylase (HDAC) inhibitor, induces the expression of fetal hemoglobin in primary erythroid cells and is therefore an excellent candidate for further pre-clinical development in sickle cell disease. In this project, we are performing a dose escalation pharmacodynamic study of vorinostat in a phlebotomized cynomolgus macaque primate model, the model used to establish the efficacy of hydroxyurea. We will examine the effects of vorinostat on globin mRNA levels (with quantitative PCR), fetal hemoglobin protein levels (with high protein liquid chromatography (HPLC)), F cell frequency (with flow cytometry), globin locus acetylation, and red blood cell rheology. We will start by treating one animal with escalating doses of vorinostat, and subsequently plan to combine vorinostat with hydroxyurea to evaluate for possible additive benefit.