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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-02-0589. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-02-0589v1 100/5/1662    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 Nathwani, A. C. Articles by Nienhuis, A. W. Search for Related Content PubMed PubMed Citation Articles by Nathwani, A. C. Articles by Nienhuis, A. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2002, Vol. 100, No. 5, pp. 1662-1669 GENE THERAPY Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques Amit C. Nathwani, Andrew M. Davidoff, Hideki Hanawa, Yunyu Hu, Fredric A. Hoffer, Alexander Nikanorov, Clive Slaughter, Catherine Y. C. Ng, Junfang Zhou, Jay N. Lozier, Timothy D. Mandrell, Elio F. Vanin, and Arthur W. Nienhuis From the Department of Haematology, University College London, United Kingdom; National Blood Authority, United Kingdom; Department of Surgery, Division of Experimental Hematology, Diagnostic Imaging, and Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN; Food and Drug Administration Center for Biologics Evaluation and Research, Bethesda, MD; and Department of Comparative Medicine, University of Tennessee Health Science Center, Memphis. The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 × 1012 vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. © 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: F. Mingozzi, N. C. Hasbrouck, E. Basner-Tschakarjan, S. A. Edmonson, D. J. Hui, D. E. Sabatino, S. Zhou, J. F. Wright, H. Jiang, G. F. Pierce, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver Blood, October 1, 2007; 110(7): 2334 - 2341. [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] A. C. Nathwani, J. T. Gray, J. 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	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020