Chicago Comprehensive Sickle Cell Center: Basic & Translational Research Program

芝加哥综合镰状细胞中心：基础

• 批准号: 7640595
• 负责人: JOSEPH DESIMONE
• 金额: $ 182.36万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-18 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640595
• 关键词: Chicago; Comprehensive; Sickle; Cell; Center

DESCRIPTION (provided by applicant): 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. (End of Abstract)

描述（由申请人提供）： CCSCC 代表三个机构之间的合作联盟：伊利诺伊大学芝加哥分校 (UIC)、儿童纪念医院 (CMH) 和芝加哥大学科默儿童医院 (UCH)。 CCSCC 的使命是通过以下三项措施改善镰状细胞病患者的健康、生活质量和寿命：1) 旨在改善镰状细胞病治疗的临床和转化研究； 2）及时对患者、患者家属和社区进行诊断和教育； 3) 提供尽可能最高质量的医疗服务。该中心提出了开发镰状细胞病新疗法的主题方法，重点关注γ基因沉默的表观遗传调控。这种方法被用于三个拟议的研究项目。基础科学项目将研究DMA甲基化在基因沉默机制中的作用。研究将包括多梳蛋白、DMA 甲基转移酶 (DNMT1) 和组蛋白 H3 (Lys27) 对 DMA 甲基化的作用。翻译研究项目将重点关注新型 DNMT1 抑制剂对 DNA 低甲基化和胎儿血红蛋白诱导的影响。作为转化研究项目的一部分， FDA 批准的 DNMT1 抑制剂地西他滨的新口服制剂将在 I 期临床试验中进行测试。随后将在 II/III 期中心间协作临床试验中将口服地西他滨制剂与金标准羟基脲进行比较，以确定地西他滨是否具有临床优势。患者服务研究项目“选择”将是一项结果研究，旨在确定基于计算机的、定制的多媒体教育计划（有关生殖选择和后果）对镰状病和镰状细胞性状患者的生殖意图的影响。中心管理的总体职责将由行政核心负责。临床核心将负责为三个机构的 SCD 患者提供医疗护理、参与 CSCC 联盟开展的中心间协作临床试验以及参与转化研究项目的临床方面。患者服务核心将为 SCD 患者及其家人以及芝加哥都会区和伊利诺伊州的非专业人士和医疗社区提供以镰状细胞为重点的支持性服务。未来对 SCD 病理生理学的研究和对年轻科学家的治疗培训将通过镰状细胞学者计划得到加强。 个别项目和核心单元： 项目 1：口服地西他滨与 HU 治疗镰状细胞病的 II/III 期研究 （尤根·桑塔拉拉贾） 描述（由申请人提供）： 临床和流行病学观察，以及实验室研究的支持，表明胎儿血红蛋白 (MbF) 会干扰镰状血红蛋白 (HbS) 聚合，这促使人们尝试通过药理学 HbF 重新激活来改变镰状细胞病 (SCD)。自 1995 年以来，用于此目的的药物和有症状的 SCD 患者的护理标准一直是羟基脲 (HU)。 HU 对于 SCD 患者来说是一个巨大的进步。然而，它有许多局限性，主要是有限的响应率和有限的 HbF 升高幅度。地西他滨是一种 DNA 甲基化抑制剂，可直接解决负责产生 HbF（γ-珠蛋白）的基因被沉默的机制。迄今为止，地西他滨在所有接受治疗的 SCD 患者中产生了 100% 的缓解率，且 HbF 大幅升高。因此，地西他滨有可能为 SCD 带来更大、更广泛的益处，并且可能具有与 HU 相似或更好的毒性特征。这最终只能通过仔细进行 III/III 期临床试验来确定。在本 RFA 的时间范围内，对口服地西他滨与 HU 治疗症状性 SCD 进行随机双盲比较是可行的。假设：地西他滨具有相似的毒性特征（临床不良事件。VDJ 测定、红细胞微核测定），但在以下方面比 HU 更有效：(i) 降低危象频率：(ii) 增加与改善生存相关的标志物（HbF% 和 F 细胞） %): (iii) 改善生活质量 (QOU: (iv) 减少溶血标志物（总 Hb. 网状细胞计数. LDH.胆红素）：（v）减少肺动脉高压标志物和死亡率增加（BMP）：（vi）减少凝血途径、炎症途径和血小板活化的标志物（D-二聚体、C-反应蛋白（CRP）、可溶性 CD40-liaand (sCD40D)：(vii) 增加促红细胞生成素水平，这种激素在贫血和 SCD 治疗反应中的作用尚不清楚。这些假设将通过完成以下内容进行检验。总体目标 - 在 150 名患有 SCD 的成人中进行口服地西他滨与 HU 的 II/III 期随机双盲对照试验，以危象频率作为主要终点，将上面强调的参数作为次要终点。计划的临床和客观实验室测量可全面了解 HU 和地西他滨的病理生理影响。与镰状细胞病理生理学不同方面（例如慢性溶血、血管闭塞和凝血途径激活）相关的客观实验室参数可以与临床结果相关联，以深入了解 SCD 各种临床表现的潜在病理生理学并确认或确认反驳这些客观实验室参数作为替代临床终点的价值。一种潜在的、非常重要且有效的、具有新颖作用机制的 SCD 修饰剂将通过本试验的完成进行关键和明确的评估。 （摘要完）