Knockout-transgenic mouse models of human hemoglobinopathies

Academic Article


  • Knockout-Transgenic mice that synthesize'100% human hemoglobin in adult red blood cells have been produced. These mice are generated by interbreeding transgenic mice expressing high levels of human hemoglobins with knockout mice in which both adult ex- and β-globin genes are deleted (Paszty et al., 1995 and Ciavatta et al., 1995, respectively). We have generated mice that survive solely on human adull (HbA), fetal (HbF), sickle (HbS), and novel recombinant hemoglobins. Examples of both balanced and severely thalassemic human hemoglobin mice have been generated. This knockouttransgenic strategy should be amenable to the generation of murine models for any human hemoglobinopathy. A switching DNA construct (LCR y~βs) was required to produce the six independent sickle cell disease mouse lines (HbSl through HbS6). The timing of the fetal to adult hemoglobin switch in the LCR y-βs transgene is delayed to more closely coincide with the timing of the switch in man. Human HbF represents approximately 40% of total Hb in newborn transgenic hemolysates. This high level of HbF gradually decreases, as the pups mature, to a level of only a few percent in adult animals. Concomitant with the decrease of HbF is the onset of erythrocyte sickling and severe hemolytic anemia. Organ and tissue pathology is seen as early as three weeks of age. The levels of HbF in adult HbS mice can be manipulated in a variety of ways. Fetal hemoglobin levels have been raised relative to HbS by crossing additional transgenes into the sickle cell mice. A cross of HbF mice with several of the HbS mouse lines described above results in animals that synthesize 30% to 50% HbF with a pancellular distribution in the adult erythrocytes. Elevation of HbF to these levels is sufficient to ameliorate the anemia and much of the pathology associated with the in vivo sickling of the HbS erythrocytes. These HbS x HbF mice are healthy and appear to be cured of sickle cell disease. These HbS mice should be valuable for a variety of studies into the pathophysiology of sickle cell disease and for developing genetic strategies to correct the defect.
  • Published In

    Author List

  • Ryan TM; Ciayatta D; Townes TM
  • Start Page

  • 807
  • Volume

  • 26
  • Issue

  • 8