Perrine Susan P, Castaneda Serguei A, Boosalis Michael S, White Gary L, Jones Brandon M, Bohacek Regine
Hemoglobinopathy-Thalassemia Research Unit, Boston University School of Medicine, 80 E. Concord St., L-908, Boston, MA 02118, USA.
Ann N Y Acad Sci. 2005;1054:257-65. doi: 10.1196/annals.1345.033.
Accelerated apoptosis of erythroid progenitors in beta-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with beta+-thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one beta 0-globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.
β地中海贫血中红系祖细胞的加速凋亡是确定性治疗的一个重大障碍，因为胎儿血红蛋白诱导剂对珠蛋白链平衡的有益作用可能无法在早期就建立了程序性细胞死亡的细胞中诱导产生。因此，我们的目标是确定减少细胞凋亡的方法，并确定口服可耐受的胎儿血红蛋白基因诱导剂。开展了一项试点临床试验，以确定胎儿血红蛋白基因诱导剂（丁酸盐）和重组人促红细胞生成素（EPO）（一种延长红系细胞存活并刺激红系增殖的造血生长因子）联合使用是否会在任何地中海贫血患者中产生累加的血液学反应。对10名患者给予丁酸盐和EPO。对也能刺激红系增殖的新型胎儿血红蛋白基因诱导剂进行了药代动力学分析。β+地中海贫血患者内源性EPO水平相对较低（<145 mU/mL），对给予的EPO和丁酸盐有累加反应。至少有一个β0珠蛋白突变的患者基线HbF水平较高（>60%）且EPO水平较高（>160 mU/mL），这些患者中有四分之三仅对胎儿血红蛋白基因诱导剂有反应。一些能刺激细胞增殖的精选胎儿血红蛋白诱导短链脂肪酸衍生物也具有良好的药代动力学特性。这些研究确定了相当一部分地中海贫血患者，他们似乎需要外源性EPO才能对任何HbF诱导剂产生最佳反应，同时也确定了作用于β地中海贫血细胞和分子病理的新治疗候选药物。这两种方法现在都为β地中海贫血的可耐受确定性治疗提供了极好的潜力。
