title: Long-Term Expression of the Human CFTR Gene in Mouse Airway via Helper-Dependent Adenoviral Vector Delivery and Transient Immunosuppression.
abstract: Sustained expression of the CFTR gene is a major challenge to gene therapy with either viral or nonviral vectors with immune response to vector and transgene products. One strategy to achieve sustained CFTR expression is to modulate the host immune system through transient immunosuppression. In this study, we examined cyclophosphamide (cytoxan), dexamethasone (Dex), and a combination of cyclosporin, methylprednisolone, and azathioprine (combination) for their effects on long-term expression of the human CFTR delivered with helper-dependent adenoviral vectors in mouse airways. We found that cyclophosphamide significantly enhanced long-term expression of the transgenic human CFTR and the reporter gene LacZ by reducing host immune responses. Dex administration greatly reduced neutralizing antibody production but had no effect on transgene expression. Treatment with a combination of cyclosporin A, azathioprine, and methylprednisolone affected neither CFTR gene expression nor inflammation. Our data suggest that transient immunosuppression might be a strategy to improve sustained expression in gene therapy.
authors.affiliation: 1 Program of Physiology & Experimental Medicine, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Huibi
authors.initials: H
authors.lastname: Cao
authors.affiliation: 1 Program of Physiology & Experimental Medicine, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: 1 Program of Physiology & Experimental Medicine, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Cathleen
authors.initials: C
authors.lastname: Duan
authors.affiliation: 2 Program of Developmental & Stem Cell Biology, Hospital for Sick Children, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Kai
authors.initials: K
authors.lastname: Du
authors.affiliation: 1 Program of Physiology & Experimental Medicine, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Chan Mi
authors.initials: CM
authors.lastname: Lee
authors.affiliation: 2 Program of Developmental & Stem Cell Biology, Hospital for Sick Children, University of Toronto , Toronto, Ontario, Canada .|3 Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Herman
authors.initials: H
authors.lastname: Yeger
authors.affiliation: 1 Program of Physiology & Experimental Medicine, University of Toronto , Toronto, Ontario, Canada .|3 Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario, Canada .
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007165:Immunosuppression Therapy; D051379:Mice
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator