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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 (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 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. Social Bookmarking                   What's this? Submitted March 14, 2002 Accepted May 14, 2002 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 Biological Systems, Oxford Biomedica (UK) Ltd, Oxford, United Kingdom Molecular Immunology Unit, Institute of Child Health, London, United Kingdom Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; Department of Molecular Genetics, Institute of Opthalmology, London, United Kingdom Department of Molecular Genetics, Institute of Opthalmology, London, United Kingdom; Molecular Immunology Unit, Institute of Child Health, London, United Kingdom Renal Section, Hammersmith Campus, Imperial College of Science Technology and Medicine, London, United Kingdom * Corresponding author; email: k.binley{at}oxfordbiomedica.co.uk. 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 cell production is adjusted through 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 Epo-TAgh mice which have relative erythropoietin deficiency. We used vectors where murine Epo expression was directed by either a hypoxia responsive (OBHRE) or constitutive (CMV) promoter. Both corrected anemia, but CMV-Epo treated mice developed fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit in the anemic mice to the normal physiological level that stabilised 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 adaptative response in patients with chronic anemia. In the OBHRE-Epo treated Epo-TAgh mice we observed significant reversal of the cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit is corrected to the normal level in anemic Epo-TAgh mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved and 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. 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. 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