Abstract
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.
Highlights
IntroductionOver 1,000 mutations are known or predicted to reduce CFTR channel number (n), open probability (PO), and/or conductance (c), and 127 of these have been identified as disease-causing mutations [1]
Genetic mutations that reduce CFTR-mediated anion conductance (Ganion = nPOc ) cause cystic fibrosis (CF)
The same glands were stimulated with the b-adrenergic cocktail to stimulate CFTRdependent C-sweating, which was imaged for 30 min
Summary
Over 1,000 mutations are known or predicted to reduce CFTR channel number (n), open probability (PO), and/or conductance (c), and 127 of these have been identified as disease-causing mutations [1]. A complex set of interacting pathophysiological consequences follows large reductions in CFTR function, most resulting from defective ion and fluid transport. VX-770 was shown to improve the function of G551D in cultured cells [3], and patients having at least one G551D mutation treated with oral ivacaftor showed marked clinical improvement [4,5], leading to FDA approval of ivacaftor for use in G551D patients. Ivacaftor was shown to improve CFTR-dependent ion transport in human airway epithelial cells carrying an R117H mutation [6], and trials are underway to determine if ivacaftor will be clinically beneficial for patients with R117H-5T mutations
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