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

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Abstract
The stable introduction of a functional β-globin gene in haematopoietic stem cells could be a powerful approach to treat β-thalassaemia1 and sickle-cell disease2. Genetic approaches aiming to increase normal β-globin expression in the progeny of autologous haematopoietic stem cells3 might circumvent the limitations and risks of allogeneic cell transplants4. However, low-level expression, position effects and transcriptional silencing hampered the effectiveness of viral transduction of the human β-globin gene when it was linked to minimal regulatory sequences5. Here we show that the use of recombinant lentiviruses enables efficient transfer and faithful integration of the human β-globin gene together with large segments of its locus control region. In long-term recipients of unselected transduced bone marrow cells, tetramers of two murine α-globin and two human βA-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In β-thalassaemic heterozygous mice higher percentages are obtained (17% to 24%), which are sufficient to ameliorate anaemia and red cell morphology. Such levels should be of therapeutic benefit in patients with severe defects in haemoglobin production.