Pharmacological treatment of the ion transport defect in cystic fibrosis

Cystic fibrosis (CF) is a lethal monogenetic disease characterised by impai red water and ion transport over epithelia. The lung pathology is fatal and causes death in 95% of CF patients. The genetic basis of the disease is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The most common mutation, Delta F508, r esults in a protein that cannot properly be folded in the endoplasmic retic ulum, is destroyed and hence does not reach the apical cell membrane. This paper will discuss those pharmacological approaches that are directed at co rrecting the defect in ion transport. At present, no clinically effective d rug is available, although research has defined areas in which progress mig ht be made. These are the following: (1) the drug 4-phenylbutyrate (4PBA) i ncreases the expression of Delta F508-CFTR in the cell membrane, probably b y breaking the association between Delta F508-CFTR and a chaperone; (2) a n umber of xanthines, in particular 8-cyclopentyl-1, 3-dipropylxanthine (CPX) , are effective in activating CFTR, presumably by direct binding and also p ossibly by correcting the trafficking defect; (3) the isoflavone genistein can activate both wild-type and mutant CFTR, probably through direct bindin g to the channel; (4) purinergic agonists (ATP and UTP) can stimulate chlor ide secretion via a Ca2+-dependent chloride channel and in this way compens ate for the defect in CFTR, but stable analogues will be required before th is type of treatment has clinical significance; (5) treatment with inhaled amiloride may correct the excessive absorption of Na+ ions and water by air way epithelial cells that appears connected to the defect in CFTR; although clinical tests have not been very successful so far, amiloride analogues w ith a longer half-life may give better results. The role of CFTR in bicarbo nate secretion has not yet been established with certainty, but correction of the defect in bicarbonate secretion may be important in clinical treatme nt of the disease. Currently, major efforts are directed at de developing a pharmacological treatment of the ion transport defect in CF, but much basi c research remains to be done, in particular, with regard to the mechanism by which defective CFTR is removed in the endoplasmic reticulum by the ubiq uitin-proteasome pathway, which is a central pathway in protein production and of significance for several other diseases apart from CF.