title: Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung.
abstract: For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Department of Gene Therapy, Imperial College, London, UK.
authors.forename: E W F W
authors.initials: EW
authors.lastname: Alton
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Boyd
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Department of Gene Therapy, Imperial College, London, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Davies
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Davies
authors.affiliation: Toxicology Consult, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dayan
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Gill
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Department of Gene Therapy, Imperial College, London, UK.
authors.forename: U
authors.initials: U
authors.lastname: Griesenbach
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Department of Gene Therapy, Imperial College, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Higgins
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK.
authors.forename: S C
authors.initials: SC
authors.lastname: Hyde
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Scottish Adult Cystic Fibrosis Service, Western General Hospital, Edinburgh, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Innes
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Roslin Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: McLachlan
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: D
authors.initials: D
authors.lastname: Porteous
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK.
authors.forename: I
authors.initials: I
authors.lastname: Pringle
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Scheule
authors.affiliation: 1] UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK [2] Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Sumner-Jones
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D003131:Combined Modality Therapy; D003550:Cystic Fibrosis / Q000473:pathology / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000008:administration & dosage* / Q000633:toxicity*; D008168:Lung / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D015203:Reproducibility of Results
chemical_list: C505032:CFTR protein, human; D008055:Lipids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator