NOVEL TREATMENT STRATEGIES FOR SICKLE CELL DISEASE

点击翻译按钮获取中文摘要

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.