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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2334-2341. Prepublished online as a Blood First Edition Paper on July 3, 2007; DOI 10.1182/blood-2007-03-080093. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-080093v1 110/7/2334    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mingozzi, F. Articles by High, K. A. Search for Related Content PubMed PubMed Citation Articles by Mingozzi, F. Articles by High, K. A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 14, 2007 Accepted June 21, 2007 Modulation of tolerance to the transgene product in a non-human primate model of AAV-mediated gene transfer to liver Federico Mingozzi, Nicole C. Hasbrouck, Etiena Basner-Tschkarajan, Shyrie A. Edmonson, Daniel J. Hui, Denise E. Sabatino, Shangzhen Zhou, J. Fraser Wright, Haiyan Jiang, Glenn F Pierce, Valder R. Arruda, and Katherine A. High* Division of Hematology, Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States Howard Hughes Medical Institute, Philadelphia, PA, United States University of Pennsylvania School of Medicine, Philadelphia, PA, United States Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States Clinical Development, Avigen, Inc., Alameda, CA, United States * Corresponding author; email: high{at}email.chop.edu. Adeno-associated virus (AAV)-mediated gene transfer of Factor IX (F.IX) to the liver results in long-term expression of transgene in experimental animals, but only short-term expression in humans. Loss of F.IX expression is likely due to a cytotoxic immune response to the AAV capsid, which results in clearance of transduced hepatocytes. We used a non-human primate model to assess the safety of AAV gene transfer coupled with an anti-T cell regimen designed to block this immune response. Administration of a 3-drug regimen consisting of mycophenolate mofetil (MMF), sirolimus, and the anti-IL-2 receptor antibody daclizumab consistently resulted in formation of inhibitory antibodies to human F.IX following hepatic artery administration of an AAV-hF.IX vector, whereas a 2-drug regimen consisting only of MMF and sirolimus did not. Administration of daclizumab was accompanied by a dramatic drop in the population of CD4+, CD25+, FoxP3+ regulatory T cells (Tregs). We conclude that choice of IS regimen can modulate immune responses to the transgene product upon hepatic gene transfer in subjects not fully tolerant; and that induction of transgene tolerance may depend upon a population of antigen-specific Tregs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. D. King, A. K. M. G. Muhammad, W. Xiong, K. M. Kroeger, M. Puntel, D. Larocque, D. Palmer, P. Ng, P. R. Lowenstein, and M. G. Castro High-Capacity Adenovirus Vector-Mediated Anti-Glioma Gene Therapy in the Presence of Systemic Antiadenovirus Immunity J. Virol., May 1, 2008; 82(9): 4680 - 4684. [Abstract] [Full Text] [PDF]

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