Huo Yongliang, McConnell Sean C, Ryan Thomas M
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, AL 35294, USA.
Blood. 2009 May 7;113(19):4763-70. doi: 10.1182/blood-2008-12-197012. Epub 2009 Mar 3.
A preclinical humanized mouse model of beta thalassemia major or Cooley anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult alpha and beta globin genes were replaced with adult human alpha globin genes (alpha2alpha1) and a human fetal to adult hemoglobin (Hb)-switching cassette (gamma(HPFH)deltabeta(0)), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF (alpha(2)gamma(2)), with a small amount of human minor adult Hb, HbA2 (alpha(2)delta(2)). Completion of the human fetal to adult Hb switch after birth resulted in severe anemia marked by erythroid hyperplasia, ineffective erythropoiesis, hemolysis, and death. Similar to human patients, CA mice were rescued from lethal anemia by regular blood transfusion. Transfusion corrected the anemia and effectively suppressed the ineffective erythropoiesis, but led to iron overload. This preclinical humanized animal model of CA will be useful for the development of new transfusion and iron chelation regimens, the study of iron homeostasis in disease, and testing of cellular and genetic therapies for the correction of thalassemia.
通过在胚胎干细胞中对小鼠成年珠蛋白基因进行靶向基因置换，构建了重型β地中海贫血或库利贫血（CA）的临床前人性化小鼠模型。小鼠成年α和β珠蛋白基因分别被成人α珠蛋白基因（α2α1）和人胎儿至成人血红蛋白（Hb）转换盒（γ（HPFH）δβ（0））取代。与患有CA的人类婴儿相似，完全人性化的小鼠在出生后通过主要合成人胎儿血红蛋白HbF（α（2）γ（2））以及少量人次要成人血红蛋白HbA2（α（2）δ（2））而存活。出生后完成人胎儿至成人Hb转换导致严重贫血，其特征为红系增生、无效红细胞生成、溶血和死亡。与人类患者相似，CA小鼠通过定期输血从致命性贫血中获救。输血纠正了贫血并有效抑制了无效红细胞生成，但导致了铁过载。这种CA的临床前人性化动物模型将有助于开发新的输血和铁螯合方案、研究疾病中的铁稳态以及测试用于纠正地中海贫血的细胞和基因疗法。
