NOVEL TREATMENT STRATEGIES FOR SICKLE CELL DISEASE

镰状细胞病的新治疗策略

• 批准号: 8358012
• 负责人: Benjamin Levine Ebert
• 金额: $ 5.4万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358012
• 关键词: Acetylation; Adult; Affect; Africa; Animals; Biochemical; Birth; Cells; Clinical Research; Development; Disease; Dose; Epidemiology; Erythrocytes; Erythroid Cells; FDA approved; Fetal Hemoglobin; Flow Cytometry; Frequencies; Funding; Globin; Grant; Hematological Disease; Histone Deacetylase Inhibitor; In Vitro; Individual; Inherited; Liquid Chromatography; Macaca; Messenger RNA; Modeling; Molecular; National Center for Research Resources; New England; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacodynamics; Primates; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Rheology; Sickle Cell Anemia; Sickle Hemoglobin; Source; Translating; United States; United States National Institutes of Health; Vorinostat; base; cost; effective therapy; hydroxyurea; insight; novel; polymerization; pre-clinical; treatment strategy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 镰状细胞病 (SCD) 是一种严重的遗传性血液疾病，在美国影响约 70,000 人，在非洲每年影响超过 200,000 名新生儿。 对 SCD 分子发病机制的深刻见解转化为有效的治疗方法的速度很慢。 生化、流行病学和临床研究已最终证明，胎儿血红蛋白 (HbF) 水平的升高可抑制镰状血红蛋白的聚合并显着改善该疾病。 美国 FDA 批准的唯一治疗 SCD 的药物是羟基脲，只有 25% 的成年患者从中受益。 我们和其他人在体外积累了广泛的证据，表明伏立诺他（一种组蛋白脱乙酰酶（HDAC）抑制剂）可诱导原代红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极好候选者。 在这个项目中，我们正在静脉切开的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，该模型用于建立羟基脲的功效。 我们将检查伏立诺他对珠蛋白 mRNA 水平（通过定量 PCR）、胎儿血红蛋白水平（通过高蛋白液相色谱 (HPLC)）、F 细胞频率（通过流式细胞术）、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羟基脲结合以评估可能的附加益处。