title: Reversal of lethal alpha- and beta-thalassemias in mice by expression of human embryonic globins.
abstract: Genetic mutations that block alpha- or beta-globin gene expression in humans can result in severe and frequently lethal thalassemic phenotypes. Homozygous inactivation of the endogenous alpha- or beta-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 zeta- and -globins, respectively. The capacity of embryonic globins to fully substitute for their adult globin homologues is further demonstrated by showing that zeta- and -globins reverse the hemolytic anemia and abnormal erythrocyte morphology of mice with nonlethal forms of alpha- and beta-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.
authors.affiliation: Departments of Medicine (Hematology/Oncology), Pediatrics (Hematology), and Genetics, and the Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, USA. jeruss@mail.med.upenn.edu
authors.forename: J E
authors.initials: JE
authors.lastname: Russell
authors.forename: S A
authors.initials: SA
authors.lastname: Liebhaber
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D015316:Genetic Therapy; D005914:Globins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D013045:Species Specificity; D017085:alpha-Thalassemia / Q000235:genetics / Q000628:therapy*; D017086:beta-Thalassemia / Q000235:genetics / Q000628:therapy*
chemical_list: D005914:Globins