title: Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver.
abstract: 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.
authors.affiliation: Division of Hematology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Hasbrouck
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Shyrie A
authors.initials: SA
authors.lastname: Edmonson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: Denise E
authors.initials: DE
authors.lastname: Sabatino
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D000077561:Daclizumab; D005164:Factor IX / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000276:immunology* / Q000378:metabolism*; D008253:Macaca mulatta / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D036022:Capsid Proteins; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D005164:Factor IX; D000077561:Daclizumab; D009173:Mycophenolic Acid; D020123:Sirolimus