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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1424-1430. Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2004-06-2501. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-06-2501v1 105/4/1424    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 Rivera, V. M. Articles by Wilson, J. M. Search for Related Content PubMed PubMed Citation Articles by Rivera, V. M. Articles by Wilson, J. M. Related Collections Hematopoiesis and Stem Cells Gene Expression Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer Victor M. Rivera, Guang-ping Gao, Rebecca L. Grant, Michael A. Schnell, Philip W. Zoltick, Leonard W. Rozamus, Tim Clackson, and James M. Wilson From ARIAD Gene Therapeutics, Cambridge, MA, and the Gene Therapy Program, Division of Medical Genetics, Department of Medicine, University of Pennsylvania, Philadelphia. Gene therapy is a potential route for the delivery of secreted therapeutic proteins, but pharmacologic control of expression will generally be required for optimal safety and efficacy. Previous attempts to achieve regulated expression in largeanimal models have been thwarted by transient expression or immune responses to regulatory proteins. We evaluated the ability of the dimerizer-regulated gene expression system to achieve controlled, long-term production of erythropoietin (Epo) following intramuscular administration of adeno-associated virus (AAV) vectors to 16 primates. All animals showed dose-responsive and completely reversible elevation of Epo and hematocrit in response to the dimerizer rapamycin, or analogs with reduced immunosuppressive activity, administered intravenously or orally. Animals that received optimized dual vectors showed persistent regulated expression for the duration of the study, with no apparent immune response to Epo or the regulatory proteins. Similar results were obtained with single vectors incorporating both the Epo and regulatory genes, including those packaged into serotype 1 AAV vectors to allow use of lower viral doses. For the longest-studied animal, regulated expression has persisted for more than 6 years and 26 induction cycles. These data indicate that one-time or infrequent gene transfer followed by dimerizer regulation is a promising approach for delivery of therapeutic proteins. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Sagazio, X. Xiao, Z. Wang, M. Martari, and R. Salvatori A single injection of double-stranded adeno-associated viral vector expressing GH normalizes growth in GH-deficient mice J. Endocrinol., January 1, 2008; 196(1): 79 - 88. [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] W. Weber, W. Bacchus, M. Daoud-El Baba, and M. Fussenegger Vitamin H-regulated transgene expression in mammalian cells Nucleic Acids Res., September 27, 2007; 35(17): e116 - e116. [Abstract] [Full Text] [PDF] C. Li, M. Hirsch, A. Asokan, B. Zeithaml, H. Ma, T. Kafri, and R. J. Samulski Adeno-Associated Virus Type 2 (AAV2) Capsid-Specific Cytotoxic T Lymphocytes Eliminate Only Vector-Transduced Cells Coexpressing the AAV2 Capsid In Vivo J. Virol., July 15, 2007; 81(14): 7540 - 7547. [Abstract] [Full Text] [PDF] T. Clackson Translational Research in Academia and Industry Experimental Biology and Medicine, December 1, 2006; 231(11): 1685 - 1689. [Abstract] [Full Text] [PDF] V. W. Choi, D. M. McCarty, and R. J. Samulski Host cell DNA repair pathways in adeno-associated viral genome processing. J. Virol., November 1, 2006; 80(21): 10346 - 10356. [Abstract] [Full Text] [PDF] A. I. Nykanen, K. Pajusola, R. Krebs, M. A.I. Keranen, O. Raisky, P. K. Koskinen, K. Alitalo, and K. B. Lemstrom Common Protective and Diverse Smooth Muscle Cell Effects of AAV-Mediated Angiopoietin-1 and -2 Expression in Rat Cardiac Allograft Vasculopathy Circ. Res., June 9, 2006; 98(11): 1373 - 1380. [Abstract] [Full Text] [PDF] M. A. Denti, A. Rosa, G. D'Antona, O. Sthandier, F. G. De Angelis, C. Nicoletti, M. Allocca, O. Pansarasa, V. Parente, A. Musaro, et al. Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model PNAS, March 7, 2006; 103(10): 3758 - 3763. [Abstract] [Full Text] [PDF] A. S. Pachori, L. G. Melo, L. Zhang, S. D. Solomon, and V. J. Dzau Chronic Recurrent Myocardial Ischemic Injury Is Significantly Attenuated by Pre-Emptive Adeno-Associated Virus Heme Oxygenase-1 Gene Delivery J. Am. Coll. Cardiol., February 7, 2006; 47(3): 635 - 643. [Abstract] [Full Text] [PDF]

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