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Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

Gene Therapy volume 13, pages 1628–1638 (2006)Cite this article

Abstract

Topical gene transfer to the airways of cystic fibrosis (CF) patients has been inefficient, partly due to extracellular barriers such as sputum. In an attempt to circumvent these, we assessed whether airway epithelial cells can be transfected by intravenous (i.v.) administration of liposome-complexed or ‘naked’ oligonucleotides (ODNs). The conducting airways are the likely target for CF therapy and are supplied by the bronchial circulation. Consequently, we assessed ODN transfer in the mouse trachea and main bronchi as these are supplied by the bronchial circulation. Liposome–protamine–DNA (LPD) complexes were detected in the bronchial circulation but did not transfect conducting airway epithelial cells, even in the presence of microvascular leakage. In contrast, ‘naked’ ODNs were delivered to 17% (inter-quartile range (IQR) 10–34%) and 35% (IQR 24–59%) of epithelial cells when injected at 500 μg/animal, without and with microvascular leakage, respectively. Two types of nuclear signal were observed; punctate in cells throughout the airways (3%, IQR 2–6%, and 6%, IQR 4–7%, of cells when delivered without and with microvascular leakage, respectively) and diffuse in a small number of epithelial cells in the proximal trachea. ODNs may be relevant to CF in a variety of ways and these data suggest one way towards implementing their use.

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Acknowledgements

We would like to thank Ben Booy (Confocal Microscopy Unit, Faculty of Medicine, Imperial College) and Steve Rothery (Cardiac Medicine, Faculty of Medicine, Imperial College) for their help with the confocal microscope and image capture and Jie Zhu (Department of Gene Therapy, Faculty of Medicine, Imperial College) for her advice with the histological analysis. The study was funded by the Cystic Fibrosis Trust and an MRC Prize Studentship (EH).

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Authors and Affiliations

  1. Department of Gene Therapy, Faculty of Medicine, Imperial College, London, UK

    E Holder, U Griesenbach, P K Jeffery, D M Geddes & E W F W Alton

  2. Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    S Li

  3. Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    L Huang

  4. Department of Thoracic Medicine, Faculty of Medicine, Imperial College, London, UK

    D F Rogers

  5. UK Cystic Fibrosis Gene Therapy Consortium, UK

    E Holder, U Griesenbach, D M Geddes & E W F W Alton

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  1. E Holder
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Correspondence to U Griesenbach.

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Holder, E., Griesenbach, U., Li, S. et al. Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation. Gene Ther 13, 1628–1638 (2006). https://doi.org/10.1038/sj.gt.3302811

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  • DOI: https://doi.org/10.1038/sj.gt.3302811

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