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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-02-0605. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-02-0605v1 100/7/2406    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 Binley, K. Articles by Naylor, S. Search for Related Content PubMed PubMed Citation Articles by Binley, K. Articles by Naylor, S. Related Collections Hematopoiesis and Stem Cells Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 October 2002, Vol. 100, No. 7, pp. 2406-2413 GENE THERAPY Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy Katie Binley, Zoe Askham, Sharifah Iqball, Hayley Spearman, Leigh Martin, Mahesh de Alwis, Adrian J. Thrasher, Robin R. Ali, Patrick H. Maxwell, Susan Kingsman, and Stuart Naylor From Oxford BioMedica (UK) Ltd; Molecular Immunology Unit, Institute of Child Health, London; Department of Molecular Genetics, Institute of Ophthalmology, University College London; Renal Section, Imperial College of Science Technology and Medicine, London, United Kingdom. Anemia is a common clinical problem, and there is much interest in its role in promoting left ventricular hypertrophy through increasing cardiac workload. Normally, red blood cell production is adjusted through the regulation of erythropoietin (Epo) production by the kidney. One important cause of anemia is relative deficiency of Epo, which occurs in most types of renal disease. Clinically, this can be corrected by supplementation with recombinant Epo. Here we describe an oxygen-regulated gene therapy approach to treating homozygous erythropoietin-SV40 T antigen (Epo-TAgh) mice with relative erythropoietin deficiency. We used vectors in which murine Epo expression was directed by an Oxford Biomedica hypoxia response element (OBHRE) or a constitutive cytomegalovirus (CMV) promoter. Both corrected anemia, but CMV-Epo-treated mice acquired fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit level in anemic mice to a normal physiologic level that stabilized without resulting in polycythemia. Importantly, the OBHRE-Epo vector had no significant effect on the hematocrit of control mice. Homozygous Epo-TAgh mice display cardiac hypertrophy, a common adaptive response in patients with chronic anemia. In the OBHRE-Epo-treated Epo-TAgh mice, we observed a significant reversal of cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit level is corrected to healthy in anemic Epo-TAgh mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved, and it makes EPO gene therapy more attractive and safer in clinical settings. We envisage that this control system will allow regulated delivery of therapeutic gene products in other ischemic settings. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. El Hasnaoui-Saadani, A. Pichon, D. Marchant, P. Olivier, T. Launay, P. Quidu, M. Beaudry, A. Duvallet, J.-P. Richalet, and F. Favret Cerebral adaptations to chronic anemia in a model of erythropoietin-deficient mice exposed to hypoxia Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2009; 296(3): R801 - R811. [Abstract] [Full Text] [PDF] I. C. Macdougall Novel Erythropoiesis-Stimulating Agents: A New Era in Anemia Management Clin. J. Am. Soc. Nephrol., January 1, 2008; 3(1): 200 - 207. [Abstract] [Full Text] [PDF] K. Heinicke, O. Baum, O. O. Ogunshola, J. Vogel, T. Stallmach, D. P. Wolfer, S. Keller, K. Weber, P. D. Wagner, M. Gassmann, et al. Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R947 - R956. [Abstract] [Full Text] [PDF] N. Eliopoulos, R. F. Gagnon, M. Francois, and J. Galipeau Erythropoietin Delivery by Genetically Engineered Bone Marrow Stromal Cells for Correction of Anemia in Mice with Chronic Renal Failure J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1576 - 1584. [Abstract] [Full Text] [PDF] T. Tanaka, T. Miyata, R. Inagi, T. Fujita, and M. Nangaku Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension Am. J. Pathol., December 1, 2004; 165(6): 1979 - 1992. [Abstract] [Full Text] [PDF] J. Vogel, I. Kiessling, K. Heinicke, T. Stallmach, P. Ossent, O. Vogel, M. Aulmann, T. Frietsch, H. Schmid-Schonbein, W. Kuschinsky, et al. Transgenic mice overexpressing erythropoietin adapt to excessive erythrocytosis by regulating blood viscosity Blood, September 15, 2003; 102(6): 2278 - 2284. [Abstract] [Full Text] [PDF] J. T. Prchal Delivery on Demand -- A New Era of Gene Therapy? N. Engl. J. Med., March 27, 2003; 348(13): 1282 - 1283. [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020