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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-04-1427v1 104/12/3445    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Puthenveetil, G. Articles by Malik, P. Search for Related Content PubMed PubMed Citation Articles by Puthenveetil, G. Articles by Malik, P. Related Collections Hematopoiesis and Stem Cells Red Cells Apoptosis Plenary Papers Free Research Articles Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPERS Successful correction of the human -thalassemia major phenotype using a lentiviral vector Geetha Puthenveetil, Jessica Scholes, Denysha Carbonell, Naveen Qureshi, Ping Xia, Licheng Zeng, Shulian Li, Ying Yu, Alan L Hiti, Jiing-Kuan Yee, and Punam Malik From the Saban Research Institute, Division of Hematology-Oncology, Childrens Hospital Los Angeles, Department of Pediatrics; and the Department of Pathology, University of Southern California Keck School of Medicine and City of Hope National Medical Center. -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 to 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: One step closer to gene therapy for hemoglobinopathies Brian P. Sorrentino Blood 2004 104: 3419. [Full Text] [PDF] This article has been cited by other articles: A. Perumbeti, T. Higashimoto, F. Urbinati, R. Franco, H. J. Meiselman, D. Witte, and P. Malik A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction Blood, August 6, 2009; 114(6): 1174 - 1185. [Abstract] [Full Text] [PDF] E. Molto, A. Fernandez, and L. Montoliu Boundaries in vertebrate genomes: different solutions to adequately insulate gene expression domains Brief Funct Genomic Proteomic, July 1, 2009; 8(4): 283 - 296. [Abstract] [Full Text] [PDF] A. Miccio, R. Cesari, F. Lotti, C. Rossi, F. Sanvito, M. Ponzoni, S. J. E. Routledge, C.-M. Chow, M. N. Antoniou, and G. Ferrari In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of {beta}-thalassemia PNAS, July 29, 2008; 105(30): 10547 - 10552. [Abstract] [Full Text] [PDF] A. W. Nienhuis Development of gene therapy for blood disorders Blood, May 1, 2008; 111(9): 4431 - 4444. [Abstract] [Full Text] [PDF] P. Moi and M. Sadelain Towards the genetic treatment of {beta}-thalassemia: new disease models, new vectors, new cells Haematologica, March 1, 2008; 93(3): 325 - 330. [Full Text] [PDF] T. M. Townes Gene Replacement Therapy for Sickle Cell Disease and Other Blood Disorders Hematology, January 1, 2008; 2008(1): 193 - 196. [Abstract] [Full Text] [PDF] L. Lisowski and M. Sadelain Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in -thalassemic mice Blood, December 15, 2007; 110(13): 4175 - 4178. [Abstract] [Full Text] [PDF] F. Zhang, S. I. Thornhill, S. J. Howe, M. Ulaganathan, A. Schambach, J. Sinclair, C. Kinnon, H. B. Gaspar, M. Antoniou, and A. J. Thrasher Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells Blood, September 1, 2007; 110(5): 1448 - 1457. [Abstract] [Full Text] [PDF] L.-C. Wu, C.-W. Sun, T. M. Ryan, K. M. Pawlik, J. Ren, and T. M. Townes Correction of sickle cell disease by homologous recombination in embryonic stem cells Blood, August 15, 2006; 108(4): 1183 - 1188. [Abstract] [Full Text] [PDF] D. Rund and E. Rachmilewitz {beta}-Thalassemia N. Engl. J. Med., September 15, 2005; 353(11): 1135 - 1146. [Full Text] [PDF] D. R. Asher, A. M. Cerny, and R. W. Finberg The erythrocyte viral trap: Transgenic expression of viral receptor on erythrocytes attenuates coxsackievirus B infection PNAS, September 6, 2005; 102(36): 12897 - 12902. [Abstract] [Full Text] [PDF] P. Malik and P. I. Arumugam Gene Therapy for {beta}-Thalassemia Hematology, January 1, 2005; 2005(1): 45 - 50. [Abstract] [Full Text] [PDF] M. C. Walters Stem Cell Therapy for Sickle Cell Disease: Transplantation and Gene Therapy Hematology, January 1, 2005; 2005(1): 66 - 73. [Abstract] [Full Text] [PDF]

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