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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2003-03-0677. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0677v1 102/2/506    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 Persons, D. A. Articles by Sorrentino, B. P. Search for Related Content PubMed PubMed Citation Articles by Persons, D. A. Articles by Sorrentino, B. P. Related Collections Hematopoiesis and Stem Cells Red Cells Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2003, Vol. 102, No. 2, pp. 506-513 GENE THERAPY Successful treatment of murine -thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells Derek A. Persons, Esther R. Allay, Nobukuni Sawai, Phillip W. Hargrove, Thomas P. Brent, Hideki Hanawa, Arthur W. Nienhuis, and Brian P. Sorrentino From the Division of Experimental Hematology, Departments of Hematology and Oncology, and Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN. Successful gene therapy of -thalassemia will require replacement of the abnormal erythroid compartment with erythropoiesis derived from genetically corrected, autologous hematopoietic stem cells (HSCs). However, currently attainable gene transfer efficiencies into human HSCs are unlikely to yield sufficient numbers of corrected cells for a clinical benefit. Here, using a murine model of -thalassemia, we demonstrate for the first time that selective enrichment in vivo of transplanted, drug-resistant HSCs can be used therapeutically and may therefore be a useful approach to overcome limiting gene transfer. We used an oncoretroviral vector to transfer a methylguanine methyltransferase (MGMT) drug-resistance gene into normal bone marrow cells. These cells were transplanted into -thalassemic mice given nonmyeloablative pretransplantation conditioning with temozolomide (TMZ) and O6-benzylguanine (BG). A majority of mice receiving 2 additional courses of TMZ/BG demonstrated in vivo selection of the drug-resistant cells and amelioration of anemia, compared with untreated control animals. These results were extended using a novel -globin/MGMT dual gene lentiviral vector. Following drug treatment, normal mice that received transduced cells had an average 67-fold increase in -globin expressing red cells. These studies demonstrate that MGMT-based in vivo selection may be useful to increase genetically corrected cells to therapeutic levels in patients with -thalassemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Another advance for globin gene therapy David M. Bodine Blood 2003 102: 416. [Full Text] [PDF] This article has been cited by other articles: H. Zhao, T. I. Pestina, M. Nasimuzzaman, P. Mehta, P. W. Hargrove, and D. A. Persons Amelioration of murine {beta}-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both {gamma}-globin and the MGMT drug-resistance gene Blood, June 4, 2009; 113(23): 5747 - 5756. [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] B. Verbeek, T. D. Southgate, D. E. Gilham, and G. P. Margison O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy Br. Med. Bull., March 1, 2008; 85(1): 17 - 33. [Abstract] [Full Text] [PDF] T. Neff, B. C. Beard, and H.-P. Kiem Survival of the fittest: in vivo selection and stem cell gene therapy Blood, March 1, 2006; 107(5): 1751 - 1760. [Abstract] [Full Text] [PDF] M. L. Lucas, N. E. Seidel, C. D. Porada, J. G. Quigley, S. M. Anderson, H. L. Malech, J. L. Abkowitz, E. D. Zanjani, and D. M. Bodine Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes Blood, July 1, 2005; 106(1): 51 - 58. [Abstract] [Full Text] [PDF] Q. Li, D. W. Emery, H. Han, J. Sun, M. Yu, and G. Stamatoyannopoulos Differences of globin transgene expression in stably transfected cell lines and transgenic mice Blood, April 15, 2005; 105(8): 3346 - 3352. [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] B. P. Sorrentino One step closer to gene therapy for hemoglobinopathies Blood, December 1, 2004; 104(12): 3419 - 3419. [Full Text] [PDF] H. Hanawa, P. W. Hargrove, S. Kepes, D. K. Srivastava, A. W. Nienhuis, and D. A. Persons Extended {beta}-globin locus control region elements promote consistent therapeutic expression of a {gamma}-globin lentiviral vector in murine {beta}-thalassemia Blood, October 15, 2004; 104(8): 2281 - 2290. [Abstract] [Full Text] [PDF] R. E. Richard, M. Weinreich, K.-H. Chang, J. Ieremia, M. M. Stevenson, and C. A. Blau Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency Blood, June 15, 2004; 103(12): 4432 - 4439. [Abstract] [Full Text] [PDF] H. Hanawa, P. Hematti, K. Keyvanfar, M. E. Metzger, A. Krouse, R. E. Donahue, S. Kepes, J. Gray, C. E. Dunbar, D. A. Persons, et al. Efficient gene transfer into rhesus repopulating hematopoietic stem cells using a simian immunodeficiency virus-based lentiviral vector system Blood, June 1, 2004; 103(11): 4062 - 4069. [Abstract] [Full Text] [PDF] D. M. Bodine Gene therapy for sickle cell disease marches on Blood, December 15, 2003; 102(13): 4247 - 4247. [Full Text] [PDF]

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