Submitted December 29, 2008
Accepted February 21, 2009
Preclinical transfusion-dependent humanized mouse model of 
thalassemia major
Yongliang Huo, Sean C. McConnell, and Thomas M. Ryan*
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
* Corresponding author; email: tryan{at}uab.edu.
A preclinical humanized mouse model of 
thalassemia major or Cooley's Anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult 
and globin genes were replaced with adult human globin genes (21) and a human fetal to adult hemoglobin (Hb) switching cassette (
HPFH
0), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF (22), with a small amount of human minor adult Hb, HbA2 (22). 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 for testing cellular and genetic therapies for the correction of thalassemia.
