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

• Published in: Nature (London) Vol. 406; no. 6791; pp. 82 - 86
• Main Authors: Sadelain, Michel, May, Chad, Rivella, Stefano, Callegari, John, Heller, Glenn, Gaensler, Karen M. L, Luzzatto, Lucio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 06.07.2000; Nature Publishing Group
• Subjects: AIDS/HIV; Anemias. Hemoglobinopathies; Animals; b-globin; b-thalassemia; beta-Thalassemia - metabolism; beta-Thalassemia - therapy; Biological and medical sciences; Bone Marrow Transplantation; Cell Line; Cells; Diseases of red blood cells; Female; Gene Transfer Techniques; Genes; Genetic Therapy; Genetic Vectors; Globins - biosynthesis; Globins - genetics; Hematologic and hematopoietic diseases; Hemoglobins - biosynthesis; HIV-1 - genetics; Humans; Lentivirus; Lentivirus - genetics; Male; Medical sciences; Mice; Recombinant Proteins - genetics; Recombinant Proteins - pharmacology; Rodents; Transduction, Genetic; Viruses; Human origin; Hemoglobinopathy; Rodentia; Retroviridae; Hemopathy; Biosynthesis; Experimental study; Genetic disease; Virus; Globin; Vertebrata; Hemolytic anemia; Mammalia; Gene; Mouse; β-Thalassemia; Animal; Hemoglobin; Feasibility; Gene therapy; Vector
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35017565

The stable introduction of a functional β-globin gene in haematopoietic stem cells could be a powerful approach to treat β-thalassaemia and sickle-cell disease. Genetic approaches aiming to increase normal β-globin expression in the progeny of autologous haematopoietic stem cells might circumvent the limitations and risks of allogeneic cell transplants. 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 sequences. 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.