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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2281-2290. Prepublished online as a Blood First Edition Paper on June 15, 2004; DOI 10.1182/blood-2004-03-0863. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0863v1 104/8/2281    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 Hanawa, H. Articles by Persons, D. A. Search for Related Content PubMed PubMed Citation Articles by Hanawa, H. Articles by Persons, D. A. Related Collections Red Cells Gene Expression Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Extended -globin locus control region elements promote consistent therapeutic expression of a -globin lentiviral vector in murine -thalassemia Hideki Hanawa, Phillip W. Hargrove, Steven Kepes, Deo K. Srivastava, Arthur W. Nienhuis, and Derek A. Persons From the Division of Experimental Hematology, the Department of Hematology and Oncology, and the Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN. Since increased fetal hemoglobin diminishes the severity of -thalassemia and sickle cell anemia, a strategy using autologous, stem cell–targeted gene transfer of a -globin gene may be therapeutically useful. We previously found that a -globin lentiviral vector utilizing the -globin promoter and elements from the -globin locus control region (LCR) totaling 1.7 kb could correct murine -thalassemia. However, therapeutic consistency was compromised by chromosomal position effects on vector expression. In contrast, we show here that the majority of animals that received transplants of -thalassemic stem cells transduced with a new vector containing 3.2 kb of LCR sequences expressed high levels of fetal hemoglobin (17%-33%), with an average vector copy number of 1.3. This led to a mean 26 g/L (2.6 g/dL) increase in hemoglobin concentration and enhanced amelioration of other hematologic parameters. Analysis of clonal erythroid cells of secondary spleen colonies from mice that underwent transplantation demonstrated an increased resistance of the larger LCR vector to stable and variegating position effects. This trend was also observed for vector insertion sites located inside genes, where vector expression was often compromised, in contrast to intergenic sites, where higher levels of expression were observed. These data emphasize the importance of overcoming detrimental position effects for consistent therapeutic globin vector expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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. W. Nienhuis Development of gene therapy for blood disorders Blood, May 1, 2008; 111(9): 4431 - 4444. [Abstract] [Full Text] [PDF] B. Y. Ryu, M. V. Evans-Galea, J. T. Gray, D. M. Bodine, D. A. Persons, and A. W. Nienhuis An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation Blood, February 15, 2008; 111(4): 1866 - 1875. [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] J. C. Cheng, K. M. Sakamoto, E. M. Horwitz, S. L. Karsten, L. Shoemaker, H. I. Kornblumc, and P. Malik Report on the Workshop "New Technologies in Stem Cell Research," Society for Pediatric Research, San Francisco, California, April 29, 2006 Stem Cells, April 1, 2007; 25(4): 1070 - 1088. [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] P. Malik and P. I. Arumugam Gene Therapy for {beta}-Thalassemia Hematology, January 1, 2005; 2005(1): 45 - 50. [Abstract] [Full Text] [PDF]

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