A SHORT-TERM TRIAL OF BUTYRATE TO STIMULATE FETAL-GLOBIN GENE-EXPRESSION IN THE BETA-GLOBIN DISORDERS
A SHORT-TERM TRIAL OF BUTYRATE TO STIMULATE FETAL-GLOBIN GENE-EXPRESSION IN THE BETA-GLOBIN DISORDERS
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DOI：
10.1056/nejm199301143280202
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发表时间：
1993-01-14
影响因子：
158.5
通讯作者：
OLIVIERI, NF
中科院分区：
文献类型：
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作者：
PERRINE, SP;GINDER, GD;OLIVIERI, NF
背景。胎儿珠蛋白（γ -珠蛋白）链抑制血红蛋白S（镰状血红蛋白）的聚合，可以在功能上替代β -地中海贫血患者中有缺陷或缺失的β -珠蛋白链。因此，确定刺激胎儿血红蛋白生成的安全机制是非常有趣的。先前的研究表明，丁酸盐选择性地刺激人类胎儿珠蛋白基因的启动子，并导致发育中的胎儿、培养细胞和动物模型中γ -珠蛋白基因表达的增加。为了确定丁酸盐是否能刺激人类胎儿珠蛋白的产生，我们用短疗程静脉输注丁酸精氨酸治疗了3例镰状细胞性贫血患者（3 - 13岁）和3例β -地中海贫血综合征患者（7 - 27岁）。药物连续注射两周或三周；初始剂量为每天每公斤体重500毫克。在治疗前和治疗过程中测定球蛋白链比率、网状红细胞生成血红蛋白F （F reticulocytes）的比例和γ -球蛋白信使RNA （mRNA）水平。在所有6例患者中，胎儿珠蛋白合成比预处理水平增加了6%至45%
Background. Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin-gene expression in the developing fetus, cultured cells, and animal models.Methods. To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment.Results. In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P