RELATIONSHIP BETWEEN AIRWAY ION-TRANSPORT AND A MILD PULMONARY-DISEASE MUTATION IN CFTR

Patients with cystic fibrosis (CF) display defects in airway ion trans port, but the influence of airway transport phenotype on improved prog nosis is not known. We studied airway bioelectric properties in five C F patients with the rare A455E mutation that is associated with mild p ulmonary disease, We also evaluated five patients possessing premature truncation mutations (G542X and R553X) for which an association with mild pulmonary disease has not been as well established. We found no e vidence in vivo that a mild lung disease mutation in the CF transmembr ane regulator gene (CFTR) led to correction or partial correction of: (1) unstimulated Cl- secretion; (2) beta-agonist-activated Cl- secreti on; (3) basal sodium reabsorption; or (4) amiloride-sensitive airway s odium transport. Early phase therapeutic trials in CF, including human gene transfer trials, rely heavily on improvements in airway potentia l difference to identify promising interventions and an improved progn osis. Based on our findings in a naturally occurring group of CF patie nts with an improved pulmonary prognosis (A455E), one can argue that m arked clinical benefit might be possible without any improvement whats oever in airway bioelectric phenotype. Moreover, if genetic modifiers exist that influence the severity of a particular CFTR mutation (e.g., A455E), these may be independent of human airway Cl- secretion in viv o, since we detected minimal Cl--secretory responses in patients with A455E.