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Blood, 1 July 2006, Vol. 108, No. 1, pp. 107-115. Prepublished online as a Blood First Edition Paper on March 7, 2006; DOI 10.1182/blood-2005-12-5115. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-12-5115v1 108/1/107    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 Jiang, H. Articles by Pierce, G. F. Search for Related Content PubMed PubMed Citation Articles by Jiang, H. Articles by Pierce, G. F. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs Haiyan Jiang, David Lillicrap, Susannah Patarroyo-White, Tongyao Liu, Xiaobing Qian, Ciaran D. Scallan, Sandra Powell, Tracey Keller, Morag McMurray, Andrea Labelle, Dea Nagy, Joseph A. Vargas, Shangzhen Zhou, Linda B. Couto, and Glenn F. Pierce From Avigen, Alameda, CA; and the Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON. Hemophilia A, a deficiency of functional coagulation factor VIII (FVIII), is treated via protein replacement therapy. Restoring 1% to 5% of normal blood FVIII activity prevents spontaneous bleeding, making the disease an attractive gene therapy target. Previously, we have demonstrated short-term activity of a liver-specific AAV2 vector expressing canine B-domain-deleted FVIII (cFVIII) in a hemophilia canine model. Here, we report the long-term efficacy and safety of AAV-cFVIII vectors of serotypes 2, 5, 6, and 8 in both hemophilia A mice and dogs. AAV6-cFVIII and AAV8-cFVIII restored physiologic levels of plasma FVIII activity in hemophilia A mice. The improved efficacy is attributed to more efficient gene transfer in liver compared with AAV2 and AAV5. However, supraphysiologic cFVIII levels correlated with the formation of cFVIII-neutralizing antibodies in these mice. Of importance, hemophilia A dogs that received AAV2-cFVIII, AAV6-cFVIII, and AAV8-cFVIII have persistently expressed therapeutic levels of FVIII, without antibody formation or other toxicities, for more than 3 years. However, liver transduction efficiencies are similar between AAV2, AAV6, and AAV8 serotypes in hemophilia A dogs, in contrast to mice. In summary, this is the first report demonstrating multiyear therapeutic efficacy and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clinical studies. (Blood. 2006;108:107-115) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CAPitalizing on AAV Thierry VandenDriessche Blood 2006 108: 4-5. [Full Text] [PDF] This article has been cited by other articles: D. Stone, Y. Liu, Z.-Y. Li, R. Strauss, E. E. Finn, J. M. Allen, J. S. Chamberlain, and A. Lieber Biodistribution and Safety Profile of Recombinant Adeno-Associated Virus Serotype 6 Vectors following Intravenous Delivery J. Virol., August 1, 2008; 82(15): 7711 - 7715. [Abstract] [Full Text] [PDF] K. X. Cai, L. Y. Tse, C. Leung, P. K.H. Tam, R. Xu, and M. H. Sham Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin Clin. Cancer Res., February 1, 2008; 14(3): 939 - 949. [Abstract] [Full Text] [PDF] S. Prasad, D. Lillicrap, A. Labelle, S. Knappe, T. Keller, E. Burnett, S. Powell, and K. W. Johnson Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A Blood, January 15, 2008; 111(2): 672 - 679. [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] H. Jiang, L. B. Couto, S. Patarroyo-White, T. Liu, D. Nagy, J. A. Vargas, S. Zhou, C. D. Scallan, J. Sommer, S. Vijay, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy Blood, November 15, 2006; 108(10): 3321 - 3328. [Abstract] [Full Text] [PDF]

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