CFTR and Cystic Fibrosis Research
The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl--selective anion channel expressed in epithelial tissues. As well as a role in ion transport, CFTR is known to play a major role in the regulation of other epithelial channels as well as mucus rheology, inflammation and bacterial adherence. Mutations in CFTR lead to the genetic disease cystic fibrosis (CF) characterised by perturbation in salt and water movement in most epithelial tissues. Since the identification of the gene, more than 1000 gene mutations have been discovered.
Early transgenic mouse studies showed exciting gene therapy prospects for CF due to the apparent ease and accessibility for delivery of genes to the airway epithelium (1). However, problems encountered were more substantial than were originally expected and pharmacological manipulation of the biochemical defect may provide an alternative or complementary approach to treatment.
Various pharmacological agents have recently been investigated which could improve Cl- secretion in epithelial cells (2-7) and recent work in this laboratory includes investigations in a group of drugs which activate phosphodiesterases (PDEs). The in vivo activation of CFTR is believed to be primarily through stimulation of surface receptors that couple to adenylate cyclase and raise cellular cAMP levels. CFTR is also regulated by PDEs which catalyse the conversion of cAMP to 5’AMP. Therefore the PDEs are attractive therapeutic targets in CF, and inhibitors of which could allow cAMP levels to rise and hence potentiate the low level activity of mutant CFTR-such as ΔF508-CFTR-that spontaneously localise to the cell surface. However PDE inhibitors may also have effects in addition to activation of CFTR by this means. We have shown that the PDE5 inhibitor sildenafil (Viagra) can increase ΔF508-CFTR trafficking from the intracellular endoplasmic reticulum and Golgi apparatus to the apical membrane of tissues from transgenic CF mice(8).
Work is ongoing to elucidate the mechanism of action of sildenafil and other PDE inhibitors to ascertain how they could be used to alleviate some of the lung and intestinal symptoms seen in CF patients.