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Cystic fibrosis
Sildenafil (Viagra) corrects ΔF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis
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  1. R L Dormer1,
  2. C M Harris1,
  3. Z Clark1,
  4. M M C Pereira1,
  5. I J M Doull2,
  6. C Norez3,
  7. F Becq3,
  8. M A McPherson1
  1. 1Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
  2. 2Department of Child Health, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK
  3. 3Institut de Physiologie et Biologie Cellulaires, UMR 6187, CNRS, Université de Poitiers, France
  1. Correspondence to:
    Dr R L Dormer
    Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK; dormercardiff.ac.uk

Abstract

Background: Most patients with cystic fibrosis (CF) have a ΔF508 mutation resulting in abnormal retention of mutant gene protein (ΔF508-CFTR) within the cell. This study was undertaken to investigate ΔF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move ΔF508-CFTR to its correct location in the apical cell membrane.

Method: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay.

Results: In most untreated CF cells ΔF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37°C) resulted in recruitment of ΔF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased ΔF508-CFTR trafficking in cells from individuals with CF with a single copy ΔF508 (ΔF508/4016ins) or with a newly described CF trafficking mutation (R1283M).

Conclusions: The findings provide proof of principle for sildenafil as a ΔF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.

  • cystic fibrosis
  • sildenafil (Viagra)
  • genetics

https://doi.org/10.1136/thx.2003.019778

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    Footnotes

    • Financial support was provided by WORD, Pfizer Pharmaceuticals Group, Vaincre la Mucoviscidose (VLM), the Cystic Fibrosis Trust, UK and the Laurence Goodchild fellowship.

    • Conflicts of interest: none.

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