title: A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor.
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.
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Jessica E
authors: JE
authors: Char
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Marlene H
authors: MH
authors: Wolfe
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Hyung-Ju
authors: HJ
authors: Cho
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Il-Ho
authors: IH
authors: Park
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Jin Hyeok
authors: JH
authors: Jeong
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America.
authors: Eric
authors: E
authors: Frisbee
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Colleen
authors: C
authors: Dunn
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Zoe
authors: Z
authors: Davies
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Carlos
authors: C
authors: Milla
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Richard B
authors: RB
authors: Moss
authors: Department of Psychology, Stanford University, Stanford, California, United States of America.
authors: Ewart A C
authors: EA
authors: Thomas
authors: Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America ; Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America ; Department of Psychology, Stanford University, Stanford, California, United States of America.
authors: Jeffrey J
authors: JJ
authors: Wine
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000627:Aminophenols / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D013542:Sweat / Q000187:drug effects / Q000378:metabolism*; D013545:Sweat Glands / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000627:Aminophenols; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor