title: Intensive pharmacological immunosuppression allows for repetitive liver gene transfer with recombinant adenovirus in nonhuman primates.
abstract: Repeated administration of gene therapies is hampered by host immunity toward vectors and transgenes. Attempts to circumvent antivector immunity include pharmacological immunosuppression or alternating different vectors and vector serotypes with the same transgene. Our studies show that B-cell depletion with anti-CD20 monoclonal antibody and concomitant T-cell inhibition with clinically available drugs permits repeated liver gene transfer to a limited number of nonhuman primates with recombinant adenovirus. Adenoviral vector-mediated transfer of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene was visualized in vivo with a semiquantitative transgene-specific positron emission tomography (PET) technique, liver immunohistochemistry, and immunoblot for the reporter transgene in needle biopsies. Neutralizing antibody and T cell-mediated responses toward the viral capsids were sequentially monitored and found to be repressed by the drug combinations tested. Repeated liver transfer of the HSV1-tk reporter gene with the same recombinant adenoviral vector was achieved in macaques undergoing a clinically feasible immunosuppressive treatment that ablated humoral and cellular immune responses. This strategy allows measurable gene retransfer to the liver as late as 15 months following the first adenoviral exposure in a macaque, which has undergone a total of four treatments with the same adenoviral vector.
authors.affiliation: Gene Therapy and Hepatology Area, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain. afontanellas@unav.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.forename: Uxua
authors.initials: U
authors.lastname: Mancheño
authors.forename: María
authors.initials: M
authors.lastname: Collantes
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.forename: Carmen
authors.initials: C
authors.lastname: Unzu
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Asis
authors.initials: A
authors.lastname: Palazón
authors.forename: Cristian
authors.initials: C
authors.lastname: Smerdou
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Iván
authors.initials: I
authors.lastname: Peñuelas
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008099:Liver / Q000276:immunology*; D008212:Lymphocyte Depletion; D008251:Macaca; D016865:Reassortant Viruses; D011995:Recombination, Genetic; D000069283:Rituximab; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D007166:Immunosuppressive Agents; D000069283:Rituximab; D016559:Tacrolimus