Effects of human γ ‐globin in murine β ‐thalassaemia

Summary Murine models of β ‐thalassaemia have been used to test therapeutic globin gene vectors. However, the level of γ ‐globin expression necessary to achieve full phenotypic correction in these models is unclear. In order to address this issue, we carried out breeding and transplantation studies in murine models of β ‐thalassaemia intermedia ( Hbb th −3 /+) and severe β ‐thalassaemia major ( Hbb th −3 / Hbb th −3 ) using transgenic lines expressing various levels of human γ ‐globin. Expression of γ ‐globin RNA at a modest 7–14% of total α ‐globin RNA resulted in the selective survival of HbF(+) erythrocytes, a fivefold increase in total HbF, and a phenotypic improvement in the β ‐thalassaemia intermedia model. Full normalisation of erythrocyte indices in this model required γ ‐globin RNA expression at 27% of α ‐globin, resulting in an average 40% (6·8 g/dl) HbF. Studies using the homozygous Hbb th −3 model of lethal β ‐thalassaemia major demonstrated that even this high level of γ ‐globin expression, for reasons related to the function of the hybrid globin tetramers, could only prolong, but not fully support, survival. Taken together, these results indicate that only the heterozygous Hbb th −3 model of β ‐thalassaemia intermedia can be reliably used for the pre‐clinical assessment of γ ‐globin gene therapy vectors, as well as other means of γ ‐globin gene induction.