A pilot study of subcutaneous decitabine in β-thalassemia intermedia
A pilot study of subcutaneous decitabine in β-thalassemia intermedia
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DOI：
10.1182/blood-2011-03-341909
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发表时间：
2011-09-08
期刊：
影响因子：
20.3
通讯作者：
Vichinsky, Elliott P.
中科院分区：
文献类型：
--
作者：
Olivieri, Nancy F.;Saunthararajah, Yogen;Vichinsky, Elliott P.
无效红细胞生成是β-地中海贫血的标志，是α/非α珠蛋白链失衡的结果。(1)纠正珠蛋白链失衡的一种策略是诱导γ-珠蛋白基因（HBG）表达。成人红系细胞中HBG的抑制涉及DNA甲基化和其他表观遗传变化。因此，胞嘧啶类似物地西他滨，它可以消耗DNA甲基转移酶1（DNMT 1），可以潜在地激活HBG。在5例中间型β地中海贫血患者中，地西他滨的剂量和时间表旨在消耗DNMT 1而不引起显著的细胞毒性（0.2 mg/kg皮下注射，每周2次，持续12周）使总血红蛋白从7.88 +/- 0.88 g/dL增加至9.04 +/- 0.77 g/dL绝对胎儿血红蛋白从3.64 +/- 1.13 g/dL降至4.29 +/- 1.13 g/dL（P = .003）。溶血和红细胞密度测定指标也发生了显著的有利变化。与非细胞毒性、分化改变作用机制一致，主要副作用为血小板计数无症状性增加，无红细胞微核或VDJ重组试验证据表明具有遗传毒性。本研究在www.clinicaltrials.gov注册为#NCT 00661726。（血。2011;118（10）：2708-2711）
Ineffective erythropoiesis, the hallmark of beta-thalassemia, is a result of alpha/non-alpha globin chain imbalance.(1) One strategy to redress globin-chain imbalance is to induce gamma-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with beta-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 +/- 0.88 g/dL to 9.04 +/- 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 +/- 1.13 g/dL to 4.29 +/- 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726. (Blood. 2011;118(10):2708-2711)