Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials

Rowe, Steven M.; Accurso, Frank J.; Clancy, John

doi:10.1513/pats.200703-043br

Cited by 78 publications

(65 citation statements)

References 110 publications

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“…Genotype-to-phenotype studies correlating in vivo CFTR function, as determined by nasal potential difference techniques, with disease severity suggest that more than 10% of normal CFTR chloride transport is associated with milder CF as characterized by a lower incidence of pancreatic insufficiency, later age at diagnosis, a more moderate lung function decline, and lower sweat chloride levels (∼80 mmol/L) compared with those with minimal (<10% normal CFTR function) CFTR chloride transport (i.e., patients with F508del-homozygous CF) (41,42). The in vitro results presented here show that VX-809 increased chloride transport in cultured F508del-HBE to approximately 14% of that measured in non-CF HBE, which was sufficient to increase the ASL height.…”

Section: Discussionmentioning

confidence: 99%

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Goor

Hadida

Grootenhuis

et al. 2011

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

986

985

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC 50 , 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

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Section: Discussionmentioning

confidence: 99%

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Goor

Hadida

Grootenhuis

et al. 2011

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

986

985

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“…To investigate the relationship between CFTR functionality and sweat chloride concentration, ROWE et al [22] evaluated sweat chloride levels in CF patients as a function of predicted CFTR activity. CFTR activity was based on previous reports of the relationship between CFTR genotype and phenotype and on in vitro investigations ( fig.…”

Section: Sweat Glandmentioning

confidence: 99%

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

Derichs

2013

Eur Respir Rev

105

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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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“…A very interesting additional finding in the study of Dorfman et al is the remarkable similarity in clinical characteristics between patients homozygous for the ΔF508 CFTR mutation in CF and patients who carry 2 different exocrine pancreatic-insufficient mutations with or without ΔF508 (9). Based on in vitro and in vivo studies, it is currently believed that exocrine pancreatic-insufficient patients have 1% or less of CFTR function compared with their wild-type counterparts (13). The findings of Dorfman et al (9) tell us that the pathophysiology accompanying exocrine pancreatic insufficient mutations is essentially the same, regardless of the type of mutation.…”

Section: Phenotypic Variability and The Search For Modifier Genes In mentioning

confidence: 97%

Gene modifiers in cystic fibrosis

Accurso¹,

Sontag²

2008

J. Clin. Invest.

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Studies of modifier genes in cystic fibrosis (CF) have often been performed in small or narrowly defined populations, leading to conflicting results. In this issue of the JCI, Dorfman et al. demonstrate in a large, populationbased study that two previously studied modifier genes, coding for mannose-binding lectin 2 and TGF-β1, influence pulmonary outcome in pediatric CF patients (see the related article beginning on page 1040). They further show gene-gene interaction between the two, underscoring the complexity of CF lung disease. Their findings provide further impetus to study these molecules and associated signaling pathways in CF. In addition, these findings argue strongly for collecting genotypes of known modifiers prospectively in CF clinical trials as well as in longitudinal studies of infants identified through newborn screening, where the full impact of such modifiers can be defined more precisely.

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Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials

Cited by 78 publications

References 110 publications

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

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

Gene modifiers in cystic fibrosis

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