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A sheep lung model for evaluation of aerosol gene therapy for cystic fibrosis.

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A sheep lung model for evaluation of aerosol gene therapy for cystic fibrosis.

Realistic pre-clinical evaluation of prospective gene transfer agents (GTAs) is a critical process in developing effective gene therapy strategies for Cystic Fibrosis (CF). Gene transfer efficiency in vitro is a poor predictor of in vivo efficacy, therefore animal models are required for evaluation. Studies in the CF mouse have an important role to play as only these can inform on the ability of the gene therapy vector to achieve functional restoration of the cAMP-dependent chloride channel activity of the CFTR protein. It is unlikely however, that studies in the mouse alone will be able to predict clinical efficiency in CF patients. Clinically effective gene therapy for CF patients will require sustained expression of the CFTR protein at the apical surface. It is generally accepted that turnover of epithelial cells in the airway will result in a gradual loss of transgene expression over time unless we can target “stem” or “progenitor” cells with an integrating DNA vector. In the absence of such a strategy a successful gene transfer agent will have to be delivered repeatedly to maintain expression. Non-invasive aerosol delivery to the airway epithelium is the preferred route for administration of gene therapy vectors to CF patients. A number of reasons led us to consider the sheep as an attractive model system for aerosol delivery. Studies of the structure and cellular populations of the sheep pulmonary bronchiolar and alveolar epithelium revealed a progression from primary to secondary then terminal (tertiary) and respiratory bronchioles and in general the fine structure, localisation and composition of cellular populations of the bronchiolar and alveolar epithelium are similar to human lung. In addition recent experience in relation to assessing ovine pulmonary responses at the lung segmental and ex vivo organ culture levels prompted our investigation of this model system as a means to further develop and refine lung-directed gene transfer protocols. We have previously described studies based on instillation of gene therapy agents (GTAs) to individual segments of the sheep lung. We have now extended this to investigate whole lung aerosol delivery of GTAs. In this model, a negative pressure respiration system is used with anaesthetised sheep facilitating both inspiratory-gated aerosol delivery and bronchoscopic access with the airway under atmospheric pressure. This allows the delivery of relevant quantities of DNA in a relatively short time interval; an important factor if these studies are to be extrapolated to human clinical trials. Although no CF sheep model exists to date, the similarities to humans in lung physiology and architecture are proving to be invaluable in the assessment of gene delivery and efficacy, the localisation of transgene expression and the safety of the gene transfer protocol, all crucially relevant endpoint measurements. Data obtained from studies in the sheep have played a key role in the recent selection of a combination of GTA and plasmid DNA vector that will be taken forward into clinical trials in patients over the next few years.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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