Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung (2011)

McLachlan, G., Davidson, H., Holder, E., Davies, L. A., Pringle, I. A., Sumner-Jones, S. G., Baker, A., Tennant, P., Gordon, C., Vrettou, C., Blundell, R., Hyndman, L., Stevenson, B., Wilson, A., Doherty, A., Shaw, D. J., Coles, R. L., Painter, H. A., Cheng, S. H., Scheule, R. K., Davies, J. C., Innes, J. A., Hyde, S. C., Griesenbach, U., Alton, E. W. F. W., Boyd, A. C., Porteous, D., Gill, D. R. & Collie, D. D. S.

Gene Ther. 18(10):996-1005

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We employ both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis gene therapy. Here we report the use of a large animal model to assess three non-viral GTAs: 25kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle (NP) formulated with polyethylene glycol (PEG)-substituted lysine 30-mer. GTAs complexed with plasmids expressing human CFTR cDNA were administered to the sheep lung (n=8/group) by aerosol. All GTAs gave evidence of gene transfer and expression one day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (2 out of 8) and PEI (1 out of 8). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion, that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.