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Blood, 22 January 2009, Vol. 113, No. 4, pp. 797-806. Prepublished online as a Blood First Edition Paper on October 28, 2008; DOI 10.1182/blood-2008-10-181479. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-10-181479v1 113/4/797    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Niemeyer, G. P. Articles by Lothrop, C. D. Search for Related Content PubMed PubMed Citation Articles by Niemeyer, G. P. Articles by Lothrop, C. D., Jr Related Collections Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy Glenn P. Niemeyer1,2, Roland W. Herzog3, Jane Mount1, Valder R. Arruda4, D. Michael Tillson5, John Hathcock5, Frederik W. van Ginkel6, Katherine A. High4, and Clinton D. Lothrop, Jr1,2,5 1 Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL; 2 Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham; 3 Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville; 4 Departments of Pediatrics and Medicine and Howard Hughes Medical Institute, University of Pennsylvania Medical Center and The Children's Hospital of Philadelphia; 5 Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL; and 6 Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)–mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification–mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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