title: Optimizing aerosol gene delivery and expression in the ovine lung.
abstract: We have developed the sheep as a large animal model for optimizing cystic fibrosis gene therapy protocols. We administered aerosolized gene transfer agents (GTAs) to the ovine lung in order to test the delivery, efficacy, and safety of GTAs using a clinically relevant nebulizer. A preliminary study demonstrated GTA distribution and reporter gene expression throughout the lung after aerosol administration of plasmid DNA (pDNA):GL67 and pDNA:PEI complexes. A more comprehensive study examined the dose-response relationship for pDNA:PEI and assessed the influence of adjunct therapeutic agents. We found that the sheep model can differentiate between doses of GTA and that the anticholinergic, glycopyrrolate, enhanced transgene expression. Dose-related toxicity of GTA was reduced by aerosol administration compared to direct instillation. This large animal model will allow us to move toward clinical studies with greater confidence.
authors.affiliation: Medical Genetics Section, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. gerry.mclachlan@ed.ac.uk
authors.forename: Gerry
authors.initials: G
authors.lastname: McLachlan
authors.forename: Alison
authors.initials: A
authors.lastname: Baker
authors.forename: Peter
authors.initials: P
authors.lastname: Tennant
authors.forename: Catherine
authors.initials: C
authors.lastname: Gordon
authors.forename: Christina
authors.initials: C
authors.lastname: Vrettou
authors.forename: Louise
authors.initials: L
authors.lastname: Renwick
authors.forename: Richard
authors.initials: R
authors.lastname: Blundell
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Ron K
authors.initials: RK
authors.lastname: Scheule
authors.forename: Lee
authors.initials: L
authors.lastname: Davies
authors.forename: Hazel
authors.initials: H
authors.lastname: Painter
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Coles
authors.forename: Anna E
authors.initials: AE
authors.lastname: Lawton
authors.forename: Chris
authors.initials: C
authors.lastname: Marriott
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gill
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Hyde
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Boyd
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: D David S
authors.initials: DD
authors.lastname: Collie
mesh_terms: D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000009:adverse effects / Q000295:instrumentation*; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D008168:Lung / Q000378:metabolism*; D008171:Lung Diseases / Q000209:etiology / Q000473:pathology; D008297:Male; D009330:Nebulizers and Vaporizers; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012756:Sheep
chemical_list: D011993:Recombinant Fusion Proteins; D015500:Chloramphenicol O-Acetyltransferase