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SUMMARY:A sheep lung model for evaluation of aerosol gene therapy for cyst
 ic fibrosis. - Dr Gerry McLachlan\, Wellcome Centre for Research in Compar
 ative Respiratory Medicine\, University of Edinburgh
DTSTART:20070307T163000Z
DTEND:20070307T173000Z
UID:TALK6273@talks.cam.ac.uk
CONTACT:4872
DESCRIPTION:A sheep lung model for evaluation of aerosol gene therapy for 
 cystic fibrosis.\n\nRealistic 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 v
 itro is a poor predictor of in vivo efficacy\, therefore animal models are
  required for evaluation. Studies in the CF mouse have an important role t
 o play as only these can inform on the ability of the gene therapy vector 
 to achieve functional restoration of the cAMP-dependent chloride channel a
 ctivity of the CFTR protein. It is unlikely however\, that studies in the 
 mouse alone will be able to predict clinical efficiency in CF patients. Cl
 inically effective gene therapy for CF patients will require sustained exp
 ression of the CFTR protein at the apical surface. It is generally accepte
 d 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 therap
 y 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 struct
 ure and cellular populations of the sheep pulmonary bronchiolar and alveol
 ar epithelium revealed a progression from primary to secondary then termin
 al (tertiary) and respiratory bronchioles and in general the fine structur
 e\, localisation and composition of cellular populations of the bronchiola
 r and alveolar epithelium are similar to human lung. In addition recent ex
 perience in relation to assessing ovine pulmonary responses at the lung se
 gmental and ex vivo organ culture levels prompted our investigation of thi
 s model system as a means to further develop and refine lung-directed gene
  transfer protocols. We have previously described studies based on instill
 ation of gene therapy agents (GTAs) to individual segments of the sheep lu
 ng. We have now extended this to investigate whole lung aerosol delivery o
 f GTAs. In this model\, a negative pressure respiration system is used wit
 h 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 t
 ime 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 local
 isation of transgene expression and the safety of the gene transfer protoc
 ol\, all crucially relevant endpoint measurements. Data obtained from stud
 ies in the sheep have played a key role in the recent selection of a combi
 nation of GTA and plasmid DNA vector that will be taken forward into clini
 cal trials in patients over the next few years.\n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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