CFTR Cl− channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis

Hirtz, Stephanie; Gonska, Tanja; Seydewitz, H. H.; Thomas, Jörg; Greiner, Peter; Kuehr, Joachim; Brandis, M.; Eichler, Irmgard; Rocha, Henrique; Lopes, Ana—Isabel; Barreto, Celeste; Ramalho, Anabela S.; Amaral, Margarida D.; Kunzelmann, Karl; Mall, Marcus

doi:10.1053/j.gastro.2004.07.006

Cited by 122 publications

(140 citation statements)

References 49 publications

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“…genet.sickkids.on.ca/cftr/app). Furthermore, the sweat chloride level, a parameter directly reflecting CFTR activity in vivo and thus a widely used diagnostic tool for CF, in patients taking Vx-770 (19,20) were still higher than those found in patients with mild-form CF (19,20,40), suggesting that Vx-770 alone is insufficient to completely rectify the dysfunction associated with the G551D mutation in vivo. Furthermore, recent clinical trials suggest that treatments with drugs that can improve the trafficking of ΔF508-CFTR may not be sufficient to ameliorate the clinical symptoms in patient carrying the ΔF508 mutation (1) presumably because this most common pathogenic mutation causes deficits in both membrane expression and gating (41)(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 95%

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle

Jih

Hwang

2013

Proc. Natl. Acad. Sci. U.S.A.

184

229

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Vx-770 (Ivacaftor), a Food and Drug Administration (FDA)-approved drug for clinical application to patients with cystic fibrosis (CF), shifts the paradigm from conventional symptomatic treatments to therapeutics directly tackling the root of the disease: functional defects of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel caused by pathogenic mutations. The underlying mechanism for the action of Vx-770 remains elusive partly because this compound not only increases the activity of wild-type (WT) channels whose gating is primarily controlled by ATP binding/hydrolysis, but also improves the function of G551D-CFTR, a disease-associated mutation that abolishes CFTR's responsiveness to ATP. Here we provide a unified theory to account for this dual effect of Vx-770. We found that Vx-770 enhances spontaneous, ATP-independent activity of WT-CFTR to a similar magnitude as its effects on G551D channels, a result essentially explaining Vx-770's effect on G551D-CFTR. Furthermore, Vx-770 increases the open time of WT-CFTR in an [ATP]-dependent manner. This distinct kinetic effect is accountable with a newly proposed CFTR gating model depicting an [ATP]-dependent "reentry" mechanism that allows CFTR shuffling among different open states by undergoing multiple rounds of ATP hydrolysis. We further examined the effect of Vx-770 on R352C-CFTR, a unique mutant that allows direct observation of hydrolysis-triggered gating events. Our data corroborate that Vx-770 increases the open time of WT-CFTR by stabilizing a posthydrolytic open state and thereby fosters decoupling between the gating cycle and ATP hydrolysis cycle. The current study also suggests that this unique mechanism of drug action can be further exploited to develop strategies that enhance the function of CFTR.

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Section: Discussionmentioning

confidence: 95%

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle

Jih

Hwang

2013

Proc. Natl. Acad. Sci. U.S.A.

184

229

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“…The degree of CFTR activity in the intestine can be measured using an electrophysiological test: the intestinal current measurement (ICM) [62]. Studies have shown that ICM correlates with CFTR genotype and phenotype [63], and diagnostic sensitivity in difficult CF diagnosis remarkably reaches 100% [64], making this tool also a potentially useful CF biomarker. Notably, defects in CFTR-mediated chloride transport correlated with CF disease severity, suggesting that ICM accurately reflects the level of CFTR functionality.…”

Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

101

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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“…No studies were found on reliability. ICM has been shown to discriminate between patients with cystic fibrosis and healthy individuals [37,[80][81][82][83][84][85][86]] and, at a group level, can discriminate between pancreatic sufficient and insufficient patients [35]. Similar to the sweat test and the NPD, patients with cystic fibrosis who were grouped according to their ICM result have been shown to differ in disease presentation: the more chloride secretion measured in the rectal mucosa, the milder the disease presentation [35,37,82].…”

Section: Clinimetrics Of Cftr Bio-assaysmentioning

confidence: 99%

CFTR biomarkers: time for promotion to surrogate end-point

Boeck

Kent

Davies

et al. 2012

European Respiratory Journal

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In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis.Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts.The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed.This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

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CFTR Cl− channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis

Cited by 122 publications

References 49 publications

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

CFTR biomarkers: time for promotion to surrogate end-point

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