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

• Published in: Blood Vol. 110; no. 7; pp. 2334 - 2341
• Main Authors: Mingozzi, Federico, Hasbrouck, Nicole C., Basner-Tschakarjan, Etiena, Edmonson, Shyrie A., Hui, Daniel J., Sabatino, Denise E., Zhou, Shangzhen, Wright, J. Fraser, Jiang, Haiyan, Pierce, Glenn F., Arruda, Valder R., High, Katherine A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-10-2007; The Americain Society of Hematology; American Society of Hematology
• Series: Gene Therapy
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; B-Lymphocytes - metabolism; Biological and medical sciences; Capsid Proteins - genetics; Capsid Proteins - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; Daclizumab; Factor IX - genetics; Factor IX - metabolism; Gene Expression; Gene Therapy; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors - genetics; Hematologic and hematopoietic diseases; Humans; Immune Tolerance - immunology; Immunoglobulin G - pharmacology; Immunosuppressive Agents - pharmacology; Liver - immunology; Liver - metabolism; Macaca mulatta - genetics; Macaca mulatta - metabolism; Male; Medical sciences; Models, Animal; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacology; Receptors, Interleukin-2 - immunology; Sirolimus - pharmacology; Transgenes - genetics; Hematology; Digestive system; Liver; Nonhuman primate; Tolerance; Dependovirus; Transgene; Genetic transfer; Virus; Parvoviridae; Modulation; Models; Parvovirinae
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-03-080093

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.