title: Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.
abstract: Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.
authors.affiliation: Pediatric Surgery Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Unzu
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.|Department of Oncology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Melero
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sampedro
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: U
authors.initials: U
authors.lastname: Mancheño
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Morales-Kastresana
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Serrano-Mendioroz
authors.affiliation: Research Center, Hospital Universitario 12 de Octubre, University Complutense of Madrid, Madrid, Spain.
authors.forename: R E
authors.initials: RE
authors.lastname: de Salamanca
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.|Department of Radiology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Benito
authors.affiliation: Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.|CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006378:Helper Viruses / Q000235:genetics*; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000096:biosynthesis / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008252:Macaca fascicularis; D008297:Male; D019076:Transgenes
chemical_list: D007166:Immunosuppressive Agents; D011163:Hydroxymethylbilane Synthase