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

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 i...

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Bibliographic Details
Published in:Blood 2007-10, Vol.110 (7), p.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: Article
Language:English
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
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-03-080093