A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor.
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 G55...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2014
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/0401acd3a79e4cd98a0cdfc673e9e1c9 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:0401acd3a79e4cd98a0cdfc673e9e1c9 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:0401acd3a79e4cd98a0cdfc673e9e1c92021-11-18T08:33:07ZA little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor.1932-620310.1371/journal.pone.0088564https://doaj.org/article/0401acd3a79e4cd98a0cdfc673e9e1c92014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24520399/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203To 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.Jessica E CharMarlene H WolfeHyung-Ju ChoIl-Ho ParkJin Hyeok JeongEric FrisbeeColleen DunnZoe DaviesCarlos MillaRichard B MossEwart A C ThomasJeffrey J WinePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e88564 (2014) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Jessica E Char Marlene H Wolfe Hyung-Ju Cho Il-Ho Park Jin Hyeok Jeong Eric Frisbee Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Ewart A C Thomas Jeffrey J Wine A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| description |
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. |
| format |
article |
| author |
Jessica E Char Marlene H Wolfe Hyung-Ju Cho Il-Ho Park Jin Hyeok Jeong Eric Frisbee Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Ewart A C Thomas Jeffrey J Wine |
| author_facet |
Jessica E Char Marlene H Wolfe Hyung-Ju Cho Il-Ho Park Jin Hyeok Jeong Eric Frisbee Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Ewart A C Thomas Jeffrey J Wine |
| author_sort |
Jessica E Char |
| title |
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| title_short |
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| title_full |
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| title_fullStr |
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| title_full_unstemmed |
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. |
| title_sort |
little cftr goes a long way: cftr-dependent sweat secretion from g551d and r117h-5t cystic fibrosis subjects taking ivacaftor. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/0401acd3a79e4cd98a0cdfc673e9e1c9 |
| work_keys_str_mv |
AT jessicaechar alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT marlenehwolfe alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT hyungjucho alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ilhopark alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT jinhyeokjeong alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ericfrisbee alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT colleendunn alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT zoedavies alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT carlosmilla alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT richardbmoss alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ewartacthomas alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT jeffreyjwine alittlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT jessicaechar littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT marlenehwolfe littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT hyungjucho littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ilhopark littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT jinhyeokjeong littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ericfrisbee littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT colleendunn littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT zoedavies littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT carlosmilla littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT richardbmoss littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT ewartacthomas littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor AT jeffreyjwine littlecftrgoesalongwaycftrdependentsweatsecretionfromg551dandr117h5tcysticfibrosissubjectstakingivacaftor |
| _version_ |
1718421601832140800 |