title: Limitations of the murine nose in the development of nonviral airway gene transfer.
abstract: A clinical program to assess whether lipid GL67A-mediated gene transfer can ameliorate cystic fibrosis (CF) lung disease is currently being undertaken by the UK CF Gene Therapy Consortium. We have evaluated GL67A gene transfer to the murine nasal epithelium of wild-type and CF knockout mice to assess this tissue as a test site for gene transfer agents. The plasmids used were regulated by either (1) the commonly used short-acting cytomegalovirus promoter/enhancer or (2) the ubiquitin C promoter. In a study of approximately 400 mice with CF, vector-specific CF transmembrane conductance regulator (CFTR) mRNA was detected in nasal epithelial cells of 82% of mice treated with a cytomegalovirus-plasmid (pCF1-CFTR), and 62% of mice treated with an ubiquitin C-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% toward wild-type values. Within this limitation, no significant correction of the CF phenotype was detected. At the current levels of gene transfer efficiency achievable with nonviral vectors, the murine nose is of limited value as a stepping stone to human trials.
authors: Department of Gene Therapy, Imperial College at the National Heart and Lung Institute, Manresa Road, London SW3 6LR, UK. u.griesenbach@imperial.ac.uk
authors: Uta
authors: U
authors: Griesenbach
authors: Stephanie G
authors: SG
authors: Sumner-Jones
authors: Emma
authors: E
authors: Holder
authors: Felix M
authors: FM
authors: Munkonge
authors: Theresa
authors: T
authors: Wodehouse
authors: Stephen N
authors: SN
authors: Smith
authors: Marguerite Y
authors: MY
authors: Wasowicz
authors: Ian
authors: I
authors: Pringle
authors: Isabel
authors: I
authors: Casamayor
authors: Mario
authors: M
authors: Chan
authors: Rebecca
authors: R
authors: Coles
authors: Nikki
authors: N
authors: Cornish
authors: Ann
authors: A
authors: Dewar
authors: Ann
authors: A
authors: Doherty
authors: Raymond
authors: R
authors: Farley
authors: Anne-Marie
authors: AM
authors: Green
authors: Bryony L
authors: BL
authors: Jones
authors: Mia D B
authors: MD
authors: Larsen
authors: Anna E
authors: AE
authors: Lawton
authors: Michelle
authors: M
authors: Manvell
authors: Hazel
authors: H
authors: Painter
authors: Charanjit
authors: C
authors: Singh
authors: Lucinda
authors: L
authors: Somerton
authors: Barbara
authors: B
authors: Stevenson
authors: Anusha
authors: A
authors: Varathalingam
authors: Craig
authors: C
authors: Siegel
authors: Ronald K
authors: RK
authors: Scheule
authors: Seng H
authors: SH
authors: Cheng
authors: Jane C
authors: JC
authors: Davies
authors: David J
authors: DJ
authors: Porteous
authors: Deborah R
authors: DR
authors: Gill
authors: A Christopher
authors: AC
authors: Boyd
authors: Steve C
authors: SC
authors: Hyde
authors: Eric W F W
authors: EW
authors: Alton
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D003550:Cystic Fibrosis / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D008081:Liposomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009666:Nose / Q000473:pathology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D008081:Liposomes