Humanized Mouse Model of Cooley's Anemia

A novel humanized mouse model of Cooley's Anemia (CA) was generated by targeted gene replacement in embryonic stem (ES) cells. Because the mouse does not have a true fetal hemoglobin, a delayed switching human γ to β0 globin gene cassette (γβ0) was inserted directly into the murine β globin locus replacing both adult mouse β globin genes. The inserted human β0 globin allele has a mutation in the splice donor site that produces the same aberrant transcripts in mice as described in human cells. No functional human β globin polypeptide chains are produced. Heterozygous γβ0 mice suffer from microcytic anemia. Unlike previously described animal models of β thalassemia major, homozygous γβ0 mice switch from mouse embryonic globin chains to human fetal γ globin during fetal life. When bred with human α globin knockin mice, homozygous CA mice survive solely upon human fetal hemoglobin at birth. This preclinical animal model of CA can be utilized to study the regulation of globin gene expression, synthesis, and switching; the reactivation of human fetal globin gene expression; and the testing of genetic and cell-based therapies for the correction of thalassemia.