|
|||||
|
|
Optimizing aerosol gene delivery and expression in the ovine lung. |
|
| Authors: | Gerry McLachlan Alison Baker Peter Tennant Catherine Gordon Christina Vrettou Louise Renwick Richard Blundell Seng H Cheng Ron K Scheule Lee Davies Hazel Painter Rebecca L Coles Anna E Lawton Chris Marriott Deborah R Gill Stephen C Hyde Uta Griesenbach Eric W F W Alton A Christopher Boyd David J Porteous D David S Collie |
| Institution: | Medical Genetics Section, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. gerry.mclachlan@ed.ac.uk |
| 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |