Developing β-thalassemia mouse model by deleting hbb genes for therapeutic evaluation

Abstract

Abstract Introduction: Thalassemia is a group of inherited hemolytic anemias caused by defective hemoglobin synthesis, leading to shortened red blood cell lifespan, chronic anemia, and related complications. Adult hemoglobin predominantly consists of Hemoglobin A, which is composed of two α-chains and two β-chains (α2β2). An imbalance between these α and β-chains can result in the clinical manifestations of Thalassemia. This condition can be categorized into two primary types: α-thalassemia and β-thalassemia. Methods: The Hbb-bt and Hbb-bs genes, which encode two β-globin (HBB) protein isoforms, were completely deleted in B-Hbb-bt KO, Hbb-bs KO mice. Results: The complete blood count test results reveal that, in comparison to the wild-type C57BL/6N mice (+/+), there is a substantial decline in RBC, HGB, HCT, MCV, MCH and MCHC in heterozygous B-Hbb-bt KO, Hbb-bs KO mice (H/+). Conversely, these mice exhibit a significant increase in RDW, NRBC# and NRBC%. The blood smear analysis results showed that the red blood cells of heterozygous B-Hbb-bt KO, Hbb-bs KO mice (H/+) were inconsistent in size, with an enlarged central pallor. There was also a significant presence of abnormal, fragmented and nucleated red blood cells. Conclusions: The model exhibits homozygous lethality, while heterozygous mice display severe hallmark features of Mediterranean anemia and retain fertility. Consequently, the heterozygous B-Hbb-bt KO, Hbb-bs KO mice (H/+) are suitable for conducting research related to β-thalassemia.