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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3445-3453.
Prepublished online as a Blood First Edition Paper on August 3, 2004; DOI 10.1182/blood-2004-04-1427.
 Previous Article | Next Article 
Submitted April 15, 2004
Accepted July 16, 2004
Successful Correction of the Human Beta-Thalassemia Major Phenotype Using a Lentiviral Vector
Geetha Puthenveetil, Jessica Scholes, Denysha Carbonell, Ping Xia, Naveen Qureshi, Licheng Zeng, Shulian Li, Ying Yu, Alan L Hiti, Jiing-Kuan Yee, and Punam Malik*
Division of Hematology-Oncology, Department of Pediatrics, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA, USA
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
City of Hope National Medical Center, Duarte, CA, USA
Division of Hematology-Oncology, Department of Pediatrics, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA, USA; Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
* Corresponding author; email: pmalik{at}chla.usc.edu.
Beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human  -globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the -globin expression cassette. Thus far, mouse studies have shown correction of the -thalassemia-intermedia phenotype and a partial, variable correction of -thalassemia major phenotype. We tested a lentiviral vector carrying the human -globin expression cassette flanked by a chromatin insulator, in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human -globin in erythroid cells produced in in-vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes -thalassemia. The gene-corrected human -thalassemia progenitor cells were transplanted into immune-deficient mice where they underwent normal erythroid differentiation, expressed normal levels of human -globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of -globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human -thalassemia major phenotype.
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