Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin

The stable introduction of a functional beta-globin gene in haematopoietic stem cells could be a powerful approach to treat beta-thalassaemia(1) and s ickle-cell disease(2). Genetic approaches aiming to increase normal beta-gl obin expression in the progeny of autologous haematopoietic stem cells(3) m ight circumvent the limitations and risks of allogeneic cell transplants(4) . However, low-level expression, position effects and transcriptional silen cing hampered the effectiveness of viral transduction of the human beta-glo bin gene when it was linked to minimal regulatory sequences(5). Here we sho w that the use of recombinant lentiviruses enables efficient transfer and f aithful integration of the human beta-globin gene together with large segme nts of its locus control region. In long-term recipients of unselected tran sduced bone marrow cells, tetramers of two murine alpha-globin and two huma n beta(A)-globin molecules account for up to 13% of total haemoglobin in ma ture red cells of normal mice. In beta-thalassaemic heterozygous mice highe r percentages are obtained (17% to 24%), which are sufficient to ameliorate anaemia and red cell morphology. Such levels should be of therapeutic bene fit in patients with severe defects in haemoglobin production.