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Sendai virus-mediated CFTR gene transfer to the airway epithelium

Gene Therapy volume 14, pages 1371–1379 (2007)Cite this article

Abstract

The potential for gene therapy to be an effective treatment for cystic fibrosis has been hampered by the limited gene transfer efficiency of current vectors. We have shown that recombinant Sendai virus (SeV) is highly efficient in mediating gene transfer to differentiated airway epithelial cells, because of its capacity to overcome the intra- and extracellular barriers known to limit gene delivery. Here, we have identified a novel method to allow the cystic fibrosis transmembrane conductance regulator (CFTR) cDNA sequence to be inserted within SeV (SeV-CFTR). Following in vitro transduction with SeV-CFTR, a chloride-selective current was observed using whole-cell and single-channel patch-clamp techniques. SeV-CFTR administration to the nasal epithelium of cystic fibrosis (CF) mice (CftrG551D and Cftrtm1UncTgN(FABPCFTR)#Jaw mice) led to partial correction of the CF chloride transport defect. In addition, when compared to a SeV control vector, a higher degree of inflammation and epithelial damage was found in the nasal epithelium of mice treated with SeV-CFTR. Second-generation transmission-incompetent F-deleted SeV-CFTR led to similar correction of the CF chloride transport defect in vivo as first-generation transmission-competent vectors. Further modifications to the vector or the host may make it easier to translate these studies into clinical trials of cystic fibrosis.

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Acknowledgements

This study was supported by the UK Cystic Fibrosis Trust through a grant to the UK Cystic Fibrosis Gene Therapy Consortium (www.cfgenetherapy.org.uk) and a CF Trust Senior Benjamin Angel Fellowship (UG).

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Author notes

  1. S Ferrari and U Griesenbach: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gene Therapy, Faculty of Medicine, Imperial College, National Heart and Lung Institute, London, UK

    S Ferrari, U Griesenbach, R Farley, J Zhu, F M Munkonge, S N Smith, M Chan, C Singh, P K Jeffery, D M Geddes & E W F W Alton

  2. UK Cystic Fibrosis Gene Therapy Consortium,

    S Ferrari, U Griesenbach, R Farley, F M Munkonge, M Chan, C Singh, D M Geddes, D J Porteous, S C Hyde & E W F W Alton

  3. DNAVEC Corporation, Tsukuba, Ibaraki, Japan

    A Iida, J You, H Ban, M Inoue & M Hasegawa

  4. Institute for Cell and Molecular Biosciences, University Medical School, Newcastle University, Newcastle upon Tyne, UK

    A M Wright, B Verdon, B E Argent & M A Gray

  5. Medical Genetics Section, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK

    S N Smith & D J Porteous

  6. Department of Molecular and Cellular Biology, University of Queensland, Brisbane, Australia

    B Wainwright

  7. GeneMedicine Research Group, NDCLS, Oxford University, Oxford, UK

    S C Hyde

Authors
  1. S Ferrari
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Correspondence to U Griesenbach.

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Ferrari, S., Griesenbach, U., Iida, A. et al. Sendai virus-mediated CFTR gene transfer to the airway epithelium. Gene Ther 14, 1371–1379 (2007). https://doi.org/10.1038/sj.gt.3302991

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  • DOI: https://doi.org/10.1038/sj.gt.3302991

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