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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2003-02-0495. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-02-0495v1 102/7/2412    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 Grimm, D. Articles by Kay, M. A. Search for Related Content PubMed PubMed Citation Articles by Grimm, D. Articles by Kay, M. A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 October 2003, Vol. 102, No. 7, pp. 2412-2419 GENE THERAPY Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy Dirk Grimm, Shangzhen Zhou, Hiroyuki Nakai, Clare E. Thomas, Theresa A. Storm, Sally Fuess, Takashi Matsushita, James Allen, Richard Surosky, Michael Lochrie, Leonard Meuse, Alan McClelland, Peter Colosi, and Mark A. Kay From the Departments of Pediatrics and Genetics, School of Medicine, Stanford University, Stanford, CA; and Avigen, Inc, Alameda, CA. We report the generation and use of pseudotyped adeno-associated viral (AAV) vectors for the liver-specific expression of human blood coagulation factor IX (hFIX). Therefore, an AAV-2 genome encoding the hfIX gene was cross-packaged into capsids of AAV types 1 to 6 using efficient, large-scale technology for particle production and purification. In immunocompetent mice, the resultant vector particles expressed high hFIX levels ranging from 36% (AAV-4) to more than 2000% of normal (AAV-1, -2, and -6), which would exceed curative levels in patients with hemophilia. Expression was dose- and time-dependent, with AAV-6 directing the fastest and strongest onset of hFIX expression at all doses. Interestingly, systemic administration of 2 x 1012 vector particles of AAV-1, -4, or -6 resulted in hFIX levels similar to those achieved by portal vein delivery. For all other serotypes and particle doses, hepatic vector administration yielded up to 84-fold more hFIX protein than tail vein delivery, corroborated by similarly increased vector DNA copy numbers in the liver, and elicited a reduced immune response against the viral capsids. Finally, neutralization assays showed variable immunologic cross-reactions between most of the AAV serotypes. Our technology and findings should facilitate the development of AAV pseudotype-based gene therapies for hemophilia B and other liver-related diseases. (Blood. 2003;102:2412-2419) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Grimm, J. S. Lee, L. Wang, T. Desai, B. Akache, T. A. Storm, and M. A. Kay In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses J. Virol., June 15, 2008; 82(12): 5887 - 5911. [Abstract] [Full Text] [PDF] A. C. Nathwani, J. T. Gray, J. McIntosh, C. Y. C. Ng, J. Zhou, Y. Spence, M. Cochrane, E. Gray, E. G. D. Tuddenham, and A. M. 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