![]() ![]() Previous studies by our group, 6 as well as by others, 9 7 led us to believe that human δ-globin gene activation could represent an alternative approach to the treatment of β-thalassemia and SCD. 5 To date, neither approach has led to a satisfactory, commonly accepted standard of care for hemoglobinopathies. Two main alternative strategies for the treatment of β-hemoglobinopathies are currently being investigated: (i) gene transfer of a normal β-globin gene, mostly through the use of retroviral vectors 4 3 and (ii) reactivation of the endogenous γ-globin gene that is normally expressed only during fetal life. It is, therefore, necessary to find alternative ways to treat the disease. For the majority of patients there is currently no hope for a permanent cure. ![]() Heterologous bone marrow transplantation is the only definitive cure but is currently available only for patients with a matched donor, optimally a sibling. β-thalassemia is generally fatal if not treated in the earliest years of life. 2 1 Both are chronic diseases with considerable morbidity and high mortality. Β-thalassemia and sickle cell disease (SCD) are severe hereditary anemias and are among the most common monogenic diseases worldwide. These results demonstrate, for the first time, the therapeutic potential of the δ-globin gene for treating severe hemoglobin disorders which could lead to novel approaches, not involving gene addition or reactivation, to the cure of β-hemoglobinopathies. In addition the activated δ-globin gene gives rise to a robust increase of the hemoglobin level in β-thalassemic mice, effectively improving the thalassemia phenotype. We show that the human δ-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. To evaluate the therapeutic potential we crossed the transgenic mice carrying a single copy activated δ-globin gene with a mouse model of β-thalassemia intermedia. We evaluated the activation of the Kruppel-like factor 1 containing δ-globin gene in vivo in transgenic mice. Previous in vitro results suggested the feasibility of transcriptional activation of the human δ-globin gene promoter by inserting a Kruppel-like factor 1 binding site. Although expressed at a low level, hemoglobin A2 is fully functional and could be a valid substitute of hemoglobin A in β-thalassemia, as well as an anti-sickling agent in sickle cell disease. The δ-globin gene produces the δ-globin of hemoglobin A2. To date, neither approach has led to a satisfactory, commonly accepted standard of care. Two main strategies for treatment are currently being investigated: (i) gene transfer of a normal β-globin gene (ii) reactivation of the endogenous γ-globin gene. None of the existing clinical treatments provides a solution for all patients. Β-thalassemia and sickle cell disease are widespread fatal genetic diseases. ![]()
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