In vivo activation of the human delta-globin gene: the therapeutic potential in beta-thalassemic mice

Beta-thalassemia and Sickle Cell Disease are widespread fatal genetic diseases. None of the existing clinical treatments are resolving for all patients. So far two main strategies for the treatment are being investigated: (i) gene transfer of a normal beta-globin gene; (ii) reactivation of the endogenous gamma-globin gene. To date, neither approach has led to a satisfactory, commonly accepted standard of care. The delta-globin gene produces the delta-globin of the hemoglobin A2. Although low expressed, hemoglobin A2 is fully functional and could be a valid substitute of hemoglobin A in beta-thalassemia disorder, as well as an antisickling agent in Sickle Cell Disease. Previous in vitro results suggested the feasibility to transcriptionally activate the human delta-globin gene promoter by inserting a Kruppel-like factor 1 binding site. We evaluate the activation of the Kruppel-like factor 1 containing delta-globin gene in vivo in transgenic mice. To evaluate the therapeutic potential we crossed the transgenic mice carrying a single copy activated delta-globin gene with a mouse model of beta-thalassemia intermedia. Here we show that the human delta-globin gene can be activated in vivo in a stage and tissue specific fashion simply by the insertion of a Kruppel-like factor 1 binding site into the promoter. In addiction the activated delta-globin gene gives rise to a robust increase of the hemoglobin level in beta-thalassemic mice, effectively improving the thalassemia phenotype. These results demonstrate, for the first time, the therapeutical potential of the delta-globin gene to treat severe hemoglobin disorders which could lead to novel approaches for the cure of beta-hemoglobinopathies not involving gene addiction or reactivation.