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.
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We thank M. Trudel for helpful discussion; C. Tan and H. Beauchemin for technical assistance and I. Rivière for reviewing the manuscript. This work was supported by grants from the NHLBI, the NCI, the Cancer Research Institute, the Cooley's Anaemia Foundation, DeWitt-Wallace Fund and the McDonnell Foundation Scholars Award.
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May, C., Rivella, S., Callegari, J. et al. Therapeutic haemoglobin synthesis in β-thalassaemic mice expressing lentivirus-encoded human β-globin. Nature 406, 82–86 (2000). https://doi.org/10.1038/35017565
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