NOVEL TREATMENT STRATEGIES FOR SICKLE CELL DISEASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 镰状细胞病（SCD）是一种严重的遗传性血液病，在美国每年影响约70，000人，在非洲每年影响超过200，000名新生儿。 对SCD的分子发病机制的巨大见解转化为有效治疗的速度很慢。 生物化学、流行病学和临床研究已经最终证明，胎儿血红蛋白（HbF）水平的增加抑制镰状血红蛋白的聚合并显著改善疾病。 美国FDA批准的唯一用于SCD的药物是羟基脲，只有25%的成年患者从中获益。 我们和其他人已经积累了大量的体外证据，表明伏立诺他（一种组蛋白脱乙酰酶（HDAC）抑制剂）诱导原代红系细胞中胎儿血红蛋白的表达，因此是镰状细胞病进一步临床前开发的绝佳候选药物。 在本项目中，我们正在静脉切开食蟹猴灵长类动物模型中进行伏立诺他的剂量递增药效学研究，该模型用于确定羟基脲的疗效。 我们将研究伏立诺他对珠蛋白mRNA水平（定量PCR）、胎儿血红蛋白蛋白水平（高蛋白液相色谱法（HPLC））、F细胞频率（流式细胞术）、珠蛋白位点乙酰化和红细胞流变学的影响。 我们将首先用递增剂量的伏立诺他治疗一只动物，随后计划将伏立诺他与联合收割机联合使用，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.