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Published ahead of print on July 31, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2009-0075OC
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Submitted on February 25, 2009
Accepted on July 30, 2009

Limitations of the Murine Nose in the Development of Non-viral Airway Gene Transfer

Uta Griesenbach1*, Stephanie G Sumner-Jones2, Emma Holder3, Felix M Munkonge1, Theresa Wodehouse1, Stephen N Smith1, Marguerite Y Wasowicz1, Ian Pringle2, Isabel Casamayor1, Mario Chan1, Rebecca Coles2, Nikki Cornish1, Ann Dewar4, Ann Doherty3, Raymond Farley1, Anne-Marie Green2, Bryony L Jones2, Mia DB Larsen1, Anna E Lawton2, Michelle Manvell1, Hazel Painter2, Charanjit Singh1, Lucinda Somerton1, Barbara Stevenson3, Anusha Varathalingam2, Craig Siegel5, Ronald K Scheule6, Seng H Cheng6, Jane C Davies1, David J Porteous3, Deborah R Gill2, A Christopher Boyd3, Steve C Hyde2, and Eric WFW Alton1

1 UK Cystic Fibrosis Gene Therapy Consortium, London, Oxford & Edinburgh, United Kingdom; Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, United Kingdom, 2 UK Cystic Fibrosis Gene Therapy Consortium, London, Oxford & Edinburgh, United Kingdom; Nuffield Department of Clinical Laboratory Sciences, Univesity of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, 3 UK Cystic Fibrosis Gene Therapy Consortium, London, Oxford & Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh, Edinburgh, United Kingdom, 4 Royal Brompton Elecrton Microscopy Units, London, United Kingdom, 5 Pharmaceutical Development Sciences, Genzyme Corporation, Cambridge, Massachusetts, United States, 6 Applied Discovery Research, Genzyme Corporation, Framlingham, Massachusetts, United States

* To whom correspondence should be addressed. E-mail: u.griesenbach{at}imperial.ac.uk.

A clinical programme to assess whether lipid GL67A-mediated gene-transfer can ameliorate cystic fibrosis (CF) lung disease is currently being undertaken by the UKCF Gene Therapy Consortium. We have evaluated GL67A gene transfer to the murine nasal epithelium of wildtype and CF knockout mice to assess this tissue as a test site for gene transfer agents. The plasmids used were regulated by either (a) the commonly used short-acting CMV promoter/enhancer or (b) the ubiquitin-C (UbC) promoter. In a study of approximately 400 CF mice, vector-specific CFTR mRNA was detected in nasal epithelial cells of 82% of mice treated with a CMV-plasmid (pCF1-CFTR) and 62%-of mice treated with a UbC-plasmid. We then assessed whether CFTR gene-transfer corrected a panel of CFTR-specific endpoint assays in the murine nose including ion transport, periciliary liquid height and ex vivo bacterial adherence. Importantly, even with the comparatively large number of animals assessed, the CFTR function studies were only powered to detect changes of more than 50% towards wild-type values. Within this limitation no significant correction of the CF phenotype was detected. At the currents levels of gene-transfer efficiency achievable with non-viral vectors, the murine nose is of limited value as a stepping stone to human trials.
Key words: Cystic Fibrosis • Gene Therapy • Mice • Liposomes






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