PULSE ARGININE BUTYRATE IN SICKLE CELL DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。已经证实，诱导胎儿血红蛋白（Hb F）的任何增加都可以改善镰状细胞病的临床并发症，但需要高水平（20%或更高）来防止器官损伤。化疗药物羟基脲（HU）在50%的成年患者中诱导Hb F达到8.6%的平均水平。许多患者仍然有危象和严重的并发症，但它是fda批准的治疗镰状细胞病的唯一方法。在初步研究中，在9/11成年患者中，单独使用精氨酸丁酸酯（AB）脉冲治疗方案（4天，每月一次）可将Hb F诱导至平均水平21%。当加入HU治疗时，6例患者的Hb F比单独使用HU的水平平均增加12%。HU和AB诱导Hb F的机制不同；HU通过细胞抑制作用起作用，而AB从胎儿珠蛋白基因启动子诱导转录，并可能通过抑制HDAC总体上增加基因表达。来自临床和基础研究的证据表明，这两种药物对红细胞生成活跃的患者更有效。这项开放标签的II期交叉研究将验证以下假设：1)脉冲AB会诱导比单独使用HU更高水平的Hb F， 2)影响红细胞生成率的因素评估可能会确定更可能对HU + AB有反应的患者亚群。该研究仅对单独使用HU症状未得到缓解且基线Hb F至少为2%的患者开放。患者将作为自己的对照。临床事件和血液学因素将在单独使用HU的患者中评估6个月。然后将添加AB治疗（4天，1次/月），并评估联合治疗的Hb F参数和临床事件。如果发现两种药物的叠加效应，该试验可能为选择最有可能从AB（除了HU治疗）获益的患者和设计III期试验提供依据。(这个小型试验不会作为FDA批准AB治疗镰状细胞病的关键试验

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. It has been well-established that inducing fetal hemoglobin (Hb F) by any increment can ameliorate the clinical complications of sickle cell disease, but that high levels, 20% or higher, are required to prevent organ damage. The chemotherapeutic drug Hydroxyurea (HU) induces Hb F to a mean level of 8.6% in 50% of adult patients. Many patients still have crises and serious complications on HU, but it is the only FDA-approved treatment for sickle cell disease. In pilot studies, a Pulsed regimen of Arginine Butyrate (AB) induced Hb F to a mean level of 21% in 9/11 adult patients when used alone, (4 days, once per month). When added to HU treatment, a mean increase in Hb F of 12% over levels on HU alone resulted in 6 patients. HU and AB induce Hb F through different mechanisms; HU acts through cytostatic effects, while AB induces transcription from the fetal globin gene promoter and may increase gene expression in general through HDAC inhibition. Evidence from clinical and basic studies suggests that both agents are more effective in patients with active erythropoiesis. This open-label Phase II cross-over study will test hypotheses that 1) Pulsed AB will induce higher levels of Hb F than HU alone, and 2) assessment of factors influencing erythropoietic rates may identify patient subsets who are more likely to respond to HU + AB. The study is open only to patients who have not had resolution of their symptoms with HU alone, and have a baseline Hb F of at least 2%. Patients will serve as their own controls. Clinical events and hematologic factors will be assessed in patients on HU alone for 6 months. AB therapy will then be added, (4 days, once/ month), and Hb F parameters and clinical events will be assessed on combined therapy. If additive effects are found with the two agents, the trial may provide a basis for selecting patients most likely to benefit from AB (in addition to HU therapy) and for design of Phase III trials. (This small trial will not serve as a pivotal trial for FDA approval of AB for treatment of sickle cell disease