title: Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin.
abstract: The stable introduction of a functional beta-globin gene in haematopoietic stem cells could be a powerful approach to treat beta-thalassaemia and sickle-cell disease. Genetic approaches aiming to increase normal beta-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 beta-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 beta-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 alpha-globin and two human betaA-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In beta-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.
authors.affiliation: Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: C
authors.initials: C
authors.lastname: May
authors.forename: S
authors.initials: S
authors.lastname: Rivella
authors.forename: J
authors.initials: J
authors.lastname: Callegari
authors.forename: G
authors.initials: G
authors.lastname: Heller
authors.forename: K M
authors.initials: KM
authors.lastname: Gaensler
authors.forename: L
authors.initials: L
authors.lastname: Luzzatto
authors.forename: M
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D006454:Hemoglobins / Q000096:biosynthesis*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014161:Transduction, Genetic; D017086:beta-Thalassemia / Q000378:metabolism / Q000628:therapy*
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; D005914:Globins