The CCSCC represents a collaborative consortium among three institutions, the University of Illinois at Chicago (UIC), the Children's Memorial Hospital (CMH), and the University of Chicago Comer Children's Hospital (UCH). The mission of the CCSCC is to improve the health, quality of life and longevity of persons afflicted with sickle cell disease through the triad of: 1) clinical and translational research designed to improve the treatment of sickle cell disease;2) timely diagnosis and education of patients, their families and the community;and 3) provision of the highest quality medical care possible. The Center presents a thematic approach to the development of new therapies for sickle cell disease focused on the epigenetic regulation of gamma gene silencing. This approach is utilized in three proposed research projects. The Basic Science Project will study the role of DMA methylation in the mechanism of gene silencing. Studies will include the roles of polycomb group proteins, DMA methyltransferases (DNMT1), and histone H3 (Lys27) on DMA methylation. The Translation Research Project will focus on the effect novel DNMT1 inhibitors on DNA hypomethylation and induction of fetal hemoglobin. As part of the Translational Research Project, a new oral formulation of the FDA approved DNMT1 inhibitor decitabine will be tested in a Phase I clinical trial. The oral decitabine formulation will subsequently be compared to the gold standard, hydroxyurea, in a Phase ll/lll Inter- Center Collaborative Clinical Trial to determine whether decitabine is clinically superior. The Patient Services Research Project, CHOICES, will be an outcomes study to determine the effect of a computer-based, tailored, multimedia education program concerning reproductive options and consequences, on the reproductive intentions of patients with sickle disease and sickle cell trait. Overall responsibility for the management of the Center will reside in the Administrative Core. The Clinical Core will be responsible for the medical care provided to SCD patients at the three institutions, for participation in the Inter-Center Collaborative Clinical Trials conducted by the CSCC consortium, and for participation in the clinical aspects of the Translational Research Project. The Patient Services Core will provide supportive sickle cell focused services to SCD patients and their families, as well as to the lay and medical communities of the Chicago metropolitan area and the State of Illinois. Future research into SCD pathophysiology and therapy training young scientists will be enhanced through the Sickle Cell Scholar Program. INDIVIDUAL PROJECTS AND CORE UNITS: PROJECT 1: A PHASE ll/lll STUDY OF ORAL DECITABINE VERSUS HU TO TREAT SICKLE CELL DISEASE (Yogen Saunthararajah) DESCRIPTION (provided by applicant): Clinical and epidemiologic observations, supported by bench studies demonstrating that fetal hemoglobin (MbF) interferes with sickle hemoglobin (HbS) polymerization, have motivated attempts at sickle cell disease (SCD) modification through pharmacologic HbF reactivation. Since 1995, the agent used for this purpose and the standard of care for patients with symptomatic SCD has been hydroxyurea (HU). HU has been a great advance for SCD patients. However, it has a number of limitations, primarily the limited response rate and the limited magnitude of the HbF elevations. Decitabine, an inhibitor of DNA methylation, directly addresses a mechanism by which the gene responsible for producing HbF (gamma-globin) is silenced. Decitabine has produced a 100% response rate with large HbF elevations in all SCD patients treated to date. Therefore, decitabine offers the possibility of even greater and more wide-spread benefit for SCD, possibly with a similar or better toxicity profile than HU. This can ultimately only be determined through the conduct of a careful phasell/lll clinical trial. Within the time-frame of this RFA, it would be feasible to perform a randomized double-blind comparison of oral decitabine versus HU for symptomatic SCD. Hypotheses: Decitabine has a similar toxicitv profile (clinical adverse events. VDJ assay, ervthrocvte micronucleus assay) but is more effective than HU at (i) reducing crisis frequency: (ii) increasing markers associated with improved survival (HbF% and F-cell%): (iii) improving quality of life (QOU: (iv) reducing markers of hemolvsis (total Hb. reticulocvte count. LDH. bilirubin): (v) reducing a marker of pulmonary hypertension and increased mortality (BMP): (vi) reducing markers of coagulation pathway, inflammatory pathway and platelet activation (D-Dimers. C-Reactive Protein (CRP). soluble CD40-liaand (sCD40D): (vii) increasing ervthropoietin levels, a hormone with a poorly understood role in the anemia and responses to therapy in SCD. These hypotheses will be tested through completion of the following overall aim - to conduct a phase ll/lll randomized double-blind controlled trial of oral decitabine versus HU in 150 adults with SCD with crisis frequency as the primary end-point and the parameters underlined above as secondary end-points. The planned clinical and objective laboratory measurements provide a comprehensive read-out of the pathophysiological impact of HU and decitabine. The objective laboratory parameters that relate to different aspects of sickle cell pathophysiology such as chronic hemolysis, vaso-occlusion and coagulation pathway activation can be correlated with clinical outcomes to provide insight into the underlying patho-physiology of the various clinical manifestations of SCD and confirming or refuting the value of these objective laboratory parameters as surrogate clinical end-points. A potentially very important and potent SCD modifying agent with a novel mechanism of action will be pivotally and definitively assessed through completion of this trial.
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