Hemoglobinopathies.
Hemoglobinopathies.
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DOI：
10.1182/asheducation-2003.1.14
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Adams, Robert J
中科院分区：
文献类型：
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作者：
Atweh, George F;DeSimone, Joseph;Adams, Robert J
过去二十年来，镰状细胞病患者的前景稳步改善。尽管取得了这些进步，但目前仅少数患者可以获得治愈性疗法。本章的主题是描述处于不同发展阶段的新治疗方案，这些方案可能会进一步改善这些疾病患者的前景。 Joseph DeSimone 博士和他的同事此前曾做出重要观察，即低甲基化剂 5-氮杂胞苷可以逆转成年狒狒从成年血红蛋白向胎儿血红蛋白的转变。尽管在镰状细胞病和β-地中海贫血患者中也表现出类似的活性，但对 5-氮杂胞苷毒性的担忧阻止了其在这些疾病中的广泛使用。在第一部分中，DeSimone 博士讨论了 DNA 甲基化在珠蛋白基因调控中的作用，并描述了地西他滨（5-氮杂胞苷类似物）治疗镰状细胞病患者的最新临床经验。这些令人鼓舞的研究表明，地西他滨对羟基脲无反应的患者具有显着的胎儿血红蛋白诱导活性。在第二节中，George Atweh 博士继续讨论同一主题，描述了丁酸盐（胎儿血红蛋白的另一种诱导剂）在镰状细胞病和 β 地中海贫血患者中的研究最新进展。他的部分的主要重点是使用丁酸盐和羟基脲的组合来达到更高水平的胎儿血红蛋白，这可能是完全改善这些疾病的临床表现所必需的。 Atweh 博士还描述了新颖的实验室研究，这些研究为丁酸盐诱导胎儿血红蛋白的机制提供了新的线索。在第三节中，罗纳德·内格尔博士讨论了作为人类镰状细胞病实验模型的不同可用转基因镰状小鼠。这些实验模型已经对我们对镰状细胞病病理生理学的理解产生了重大影响。 Nagel 博士描述了最近的研究，其中转基因镰状小鼠提供了第一个原理证明，即珠蛋白基因转移到造血干细胞中可以抑制体内镰状化并减轻疾病的严重程度。尽管镰状细胞病成年患者中风并不像儿童中那样常见，但成人血液学家和他们的儿科同事一样，需要对患有中风或有中风病史的成年患者做出治疗决策。罗伯特·亚当斯博士领导了几项大型临床研究，研究输血在预防镰状细胞病儿童中风方面的作用。然而，对于镰状细胞病成年患者首次或后续中风的预防知之甚少。在第四节中，亚当斯博士提供了一些治疗成年中风患者的一般指南，同时仔细区分基于证据的建议和那些本质上是轶事的建议。
The outlook for patients with sickle cell disease has improved steadily during the last two decades. In spite of these improvements, curative therapies are currently available only to a small minority of patients. The main theme of this chapter is to describe new therapeutic options that are at different stages of development that might result in further improvements in the outlook for patients with these disorders. Dr. Joseph DeSimone and his colleagues had previously made the important observation that the hypomethylating agent 5-azacytidine can reverse the switch from adult to fetal hemoglobin in adult baboons. Although similar activity was demonstrated in patients with sickle cell disease and beta-thalassemia, concern about the toxicity of 5-azacytidine prevented its widespread use in these disorders. In Section I, Dr. DeSimone discusses the role of DNA methylation in globin gene regulation and describe recent clinical experience with decitabine (an analogue of 5-azacytidine) in patients with sickle cell disease. These encouraging studies demonstrate significant fetal hemoglobin inducing activity of decitabine in patients who fail to respond to hydroxyurea. In Section II, Dr. George Atweh continues the same theme by describing recent progress in the study of butyrate, another inducer of fetal hemoglobin, in patients with sickle cell disease and beta-thalassemia. The main focus of his section is on the use of a combination of butyrate and hydroxyurea to achieve higher levels of fetal hemoglobin that might be necessary for complete amelioration of the clinical manifestations of these disorders. Dr. Atweh also describes novel laboratory studies that shed new light on the mechanisms of fetal hemoglobin induction by butyrate. In Section III, Dr. Ronald Nagel discusses the different available transgenic sickle mice as experimental models for human sickle cell disease. These experimental models have already had a significant impact on our understanding of the pathophysiology of sickle cell disease. Dr. Nagel describes more recent studies in which transgenic sickle mice provide the first proof of principle that globin gene transfer into hematopoietic stem cells inhibits in vivo sickling and ameliorates the severity of the disease. Although stroke in adult patients with sickle cell disease is not as common as in children, adult hematologists, like their pediatric colleagues, need to make management decisions in adult patients with a stroke or a history of stroke. Dr. Robert Adams has led several large clinical studies that investigated the role of transfusions in the prevention of stroke in children with sickle cell disease. Much less is known, however, about the prevention of first or subsequent strokes in adult patients with sickle cell disease. In Section IV, Dr. Adams provides some general guidelines for the management of adult patients with stroke while carefully distinguishing between recommendations that are evidence-based and those that are anecdotal in nature.