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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.
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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.
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