Rivella Stefano, May Chad, Chadburn Amy, Rivière Isabelle, Sadelain Michel
Department of Human Genetics/Medicine, the Gene Transfer and Somatic Cell Engineering Laboratory, and the Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Blood. 2003 Apr 15;101(8):2932-9. doi: 10.1182/blood-2002-10-3305. Epub 2002 Dec 12.
Patients affected by beta-thalassemia major require lifelong transfusions because of insufficient or absent production of the beta chain of hemoglobin (Hb). A minority of patients are cured by allogeneic bone marrow transplantation. In the most severe of the hitherto available mouse models of beta-thalassemia, a model for human beta-thalassemia intermedia, we previously demonstrated that globin gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0-8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic potential of gene therapy in the context of a lethal anemia, we now have created an adult model of beta(0)-thalassemia major. In this novel model, mice engrafted with beta-globin-null (Hbb(th3/th3)) fetal liver cells succumb to ineffective erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4 g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin gene transfer were rescued. Long-term chimeras with an average 1.0-2.4 copies of the TNS9 vector in their hematopoietic and blood cells stably produced up to 12 g/dL chimeric Hb consisting of mu alpha(2):hu beta(2) tetramers. Pathologic analyses indicated that erythroid maturation was restored, while EMH and iron overload dramatically decreased. Thus, we have established an adult animal model for the most severe of the hemoglobinopathies, Cooley anemia, which should prove useful to investigate both genetic and pharmacologic treatments. Our findings demonstrate the remarkable efficacy of lentivirus-mediated globin gene transfer in treating a fulminant blood disorder and strongly support the efficacy of gene therapy in the severe hemoglobinopathies.
重型β地中海贫血患者由于血红蛋白（Hb）β链生成不足或缺乏，需要终生输血。少数患者可通过异基因骨髓移植治愈。在迄今最严重的β地中海贫血小鼠模型（一种人类中间型β地中海贫血模型）中，我们先前证明，骨髓细胞中的珠蛋白基因转移具有治愈效果，可使长期嵌合体的Hb水平从8.0 - 8.5稳定提高至11.0 - 12.0 g/dL。为了在致死性贫血的背景下全面评估基因治疗的潜力，我们现在创建了一个重型β⁰地中海贫血的成年模型。在这个新模型中，移植了β-珠蛋白缺失（Hbb(th3/th3)）胎儿肝细胞的小鼠在60天内死于无效红细胞生成。这些小鼠迅速发展为严重贫血（2 - 4 g/dL）、脾肿大、髓外造血（EMH）和肝铁过载。值得注意的是，大多数（13只中的11只）接受慢病毒介导的珠蛋白基因转移治疗的小鼠获救。在其造血细胞和血细胞中平均含有1.0 - 2.4个TNS9载体拷贝的长期嵌合体稳定产生高达12 g/dL由μα₂:huβ₂四聚体组成的嵌合Hb。病理分析表明，红细胞成熟得以恢复，而EMH和铁过载显著减少。因此，我们建立了一种最严重的血红蛋白病——库利贫血的成年动物模型，这对于研究基因治疗和药物治疗都应是有用的。我们的研究结果证明了慢病毒介导的珠蛋白基因转移在治疗暴发性血液疾病方面的显著疗效，并有力地支持了基因治疗在严重血红蛋白病中的疗效。
