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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-10-3296. This Article Full Text Full Text (PDF) Erratum (v102,p788) All Versions of this Article: 2002-10-3296v1 101/8/2963    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 Manno, C. S. Articles by Glader, B. Search for Related Content PubMed PubMed Citation Articles by Manno, C. S. Articles by Glader, B. Related Collections Clinical Trials and Observations Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2003, Vol. 101, No. 8, pp. 2963-2972 GENE THERAPY AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B Catherine S. Manno, Amy J. Chew, Sylvia Hutchison, Peter J. Larson, Roland W. Herzog, Valder R. Arruda, Shing Jen Tai, Margaret V. Ragni, Arthur Thompson, Margareth Ozelo, Linda B. Couto, Debra G. B. Leonard, Frederick A. Johnson, Alan McClelland, Ciaran Scallan, Erik Skarsgard, Alan W. Flake, Mark A. Kay, Katherine A. High, and Bertil Glader From the Departments of Pediatrics, Surgery, and Pathology, University of Pennsylvania, Philadelphia; Children's Hospital of Philadelphia, PA; Avigen, Inc, Alameda, CA; Departments of Pediatrics and Surgery, Stanford University School of Medicine, Stanford, CA; Bayer Corporation Biological Products Division, Research Triangle Park, NC; Hemophilia Center of Pennsylvania, University of Pittsburgh, PA; Puget Sound Blood Center, Seattle, WA; and Hematology-Hemotherapy Center, State University of Campinas, Campinas-SP, Brazil. Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 × 1011 vector genomes (vg)/kg to 1.8 × 1012 vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals. © 2003 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: A. W. Nienhuis Development of gene therapy for blood disorders Blood, May 1, 2008; 111(9): 4431 - 4444. [Abstract] [Full Text] [PDF] K. A. High Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia Hematology, January 1, 2007; 2007(1): 466 - 472. [Abstract] [Full Text] [PDF] K.-Q. Xin, H. Mizukami, M. Urabe, Y. Toda, K. Shinoda, A. Yoshida, K. Oomura, Y. Kojima, M. 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