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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.

Original publication

DOI

10.1038/sj.mt.6300058

Type

Journal article

Journal

Mol Ther

Publication Date

02/2007

Volume

15

Pages

348 - 354

Keywords

Animals, Chloramphenicol O-Acetyltransferase, Female, Gene Expression, Gene Transfer Techniques, Genes, Reporter, Genetic Vectors, Lung, Lung Diseases, Male, Nebulizers and Vaporizers, Recombinant Fusion Proteins, Sheep