A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor

• Published in: PloS one 2014-02, Vol.9 (2), p.e88564
• Main Authors: Char, Jessica E, Wolfe, Marlene H, Cho, Hyung-Ju, Park, Il-Ho, Jeong, Jin Hyeok, Frisbee, Eric, Dunn, Colleen, Davies, Zoe, Milla, Carlos, Moss, Richard B, Thomas, Ewart A C, Wine, Jeffrey J
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); Amino Acid Substitution - genetics; Aminophenols - pharmacology; Aminophenols - therapeutic use; Analysis; Bioassays; Biology; Case-Control Studies; Chloride; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Data processing; FDA approval; Female; Glands; Humans; Laboratories; Male; Medicine; Mutation; Pediatrics; Quinolones - pharmacology; Quinolones - therapeutic use; Receptors; Secretion; Studies; Suidae; Sweat; Sweat - drug effects; Sweat - metabolism; Sweat Glands - drug effects; Sweat Glands - metabolism; Sweat Glands - pathology; Sweating; Transcription
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088564

To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (-) ivacaftor, 3 only (+) ivacaftor and 3 (+/-) ivacaftor (1-5 tests per condition). The total number of gland measurements was 852 (-) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor  = 1.6%-7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.