Reversal of Lethal - and β-Thalassemias in Mice by Expression of Human Embryonic Globins

Genetic mutations that block - or β-globin gene expression in humans can result in severe and frequently lethal thalassemic phenotypes. Homozygous inactivation of the endogenous - or β-globin genes in mice results in corresponding thalassemic syndromes that are uniformly fatal in utero. In the current study, we show that the viability of these mice can be rescued by expression of human embryonic ζ- and -globins, respectively. The capacity of embryonic globins to fully substitute for their adult globin homologues is further demonstrated by showing that ζ- and -globins reverse the hemolytic anemia and abnormal erythrocyte morphology of mice with nonlethal forms of - and β-thalassemia. These results illustrate the potential therapeutic utility of embryonic globins as substitutes for deficient adult globins in thalassemic individuals. Moreover, the capacity of embryonic globins to functionally replace their adult homologues brings into question the physiologic basis for globin gene switching.