1. Department of Human Genetics,
2. Immunology Program, and Departments of
3. Epidemiology and Biostatistics,
4. Medicine and
5. Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
6. Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA
7. Department of Medicine, University of California, San Francisco, California 94143 , USA

Correspondence to: Michel Sadelain^1,2,3,6,7 Correspondence and requests should be addressed to M.S. (e-mail:Email: m-sadelain@ski.mskcc.org).

Abstract

The stable introduction of a functional -globin gene in haematopoietic stem cells could be a powerful approach to treat -thalassaemia¹ and sickle-cell disease². Genetic approaches aiming to increase normal -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 -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 -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 -globin and two human ^A-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In -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.