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Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver

2007; Elsevier BV; Volume: 110; Issue: 7 Linguagem: Inglês

10.1182/blood-2007-03-080093

1528-0020

Federico Mingozzi, Nicole C. Hasbrouck, Etiena Basner‐Tschakarjan, Shyrie Edmonson, Daniel J. Hui, Denise E. Sabatino, Shangzhen Zhou, J. Fraser Wright, Haiyan Jiang, Glenn F. Pierce, Valder R. Arruda, Katherine A. High,

Animal Virus Infections Studies

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 nonhuman 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 immunosuppression (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 on a population of antigen-specific Tregs.