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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 17, 2008 Accepted October 18, 2008 Long term correction of inhibitor prone hemophilia B dogs treated with liver-directed AAV2 mediated factor IX gene therapy Glenn P Niemeyer, Roland W Herzog, Jane Mount, Valder R Arruda, D Michael Tillson, John Hathcock, Frederik W. van Ginkel, Katherine A High, and Clinton D Lothrop Jr* Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, United States Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, United States Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States Departments of Pediatrics and Medicine and Howard Hughes Medical Institute, University of Pennsylvania Medical Center and The Children's Hospital of Philadelphia, Philadelphia, PA, United States Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL, United States * Corresponding author; email: clothrop{at}uab.edu. Preclinical studies in mice, dogs and initial clinical trials have documented the feasibility of adeno-associated virus (AAV) mediated gene therapy for hemophilia B. In a 8 year study, inhibitor prone hemophilia B dogs (n=2) treated with liver directed AAV2 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 (WBCT, ACT, APTT) have remained at the upper limits of the normal ranges in the two dogs which received liver directed gene therapy. The FIX activity has remained stable between 4-10% in both liver treated dogs but undetectable in the dogs undergoing muscle directed gene transfer. The vector/FIX sequences have persisted in liver biopsies but were undetectable in WBC and sperm DNA. Integration site analysis by LAM-PCR suggested the vector sequences have persisted predominantly in extrachromosomal form. A complete clinical evaluation of the dogs undergoing liver directed gene therapy including CBC, serum chemistries, bile acid profile, hepatic MRI and CT scans and liver biopsy was 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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