Pharmacological Approaches to Correcting the Ion Transport Defect in Cystic Fibrosis

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Abstract
Cystic fibrosis (CF) is a lethal genetic disease caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), which mainly (but not exclusively) functions as a chloride channel. The main clinical symptoms are chronic obstructive lung disease, which is responsible for most of the morbidity and mortality associated with CF, and pancreatic insufficiency. About 1000 mutations of the gene coding for CFTR are currently known; the most common of these, present in the great majority of the patients (Δ508) results in the deletion of a phenylalanine at position 508. In this mutation, the aberrant CFTR is not transported to the membrane but degraded in the ubiquitin-proteasome pathway. The aim of this review is to give an overview of the pharmacologic strategies currently used in attempts to overcome the ion transport defect in CF. One strategy to develop pharmacologic treatment for CF is to inhibit the breakdown of ΔF508-CFTR by interfering with the chaperones involved in the folding of CFTR. At least in in vitro systems, this can be accomplished by sodium phenylbutyrate, or S-nitrosoglutathione (GSNO), and also by genistein or benzo[c]quinolizinium compounds. It is also possible to stimulate CFTR or its mutated forms, when present in the plasma membrane, using xanthines, genistein, and various other compounds, such as benzamidizoles and benzoxazoles, benzo[c]quinolizinium compounds or phenantrolines. Experimental results are not always unambiguous, and adverse effects have been incompletely tested. Some clinical tests have been done on sodium phenyl butyrate, GSNO and genistein, mostly in respect to other diseases, and the results demonstrate that these drugs are reasonably well tolerated. Their efficiency in the treatment of CF has not yet been demonstrated, however. An alternative strategy is to compensate for the defective chloride transport by CFTR by stimulation of other chloride channels. This can be done via purinergic receptors. A phase I study using a stable uridine triphosphate analog has recently been completed. A second alternative strategy is to attempt to maintain hydration of the airway mucus by inhibiting Na+ uptake by the epithelial Na+ channel using amiloride or stable analogs of amiloride. Clinical tests so far have been inconclusive. A number of other suggestions are currently being explored. The minority of patients with CF who have a stop mutation may benefit from treatment with gentamicin. The difficulties in finding a pharmacologic treatment for CF may be due to the fact that CFTR has additional functions besides chloride transport, and interfering with CFTR biosynthesis or activation implies interference with central cellular processes, which may have undesirable adverse effects.