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

Chad May, Stefano Rivella, John Callegari, Glenn Heller, Karen M. L. Gaensler, Lucio Luzzatto and Michel Sadelain ()
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Chad May: Department of Human Genetics
Stefano Rivella: Department of Human Genetics
John Callegari: Department of Human Genetics
Glenn Heller: Departments of §Epidemiology and Biostatistics
Karen M. L. Gaensler: University of California
Lucio Luzzatto: Department of Human Genetics
Michel Sadelain: Department of Human Genetics

Nature, 2000, vol. 406, issue 6791, 82-86

Abstract: 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.

Date: 2000
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DOI: 10.1038/35017565

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