Functional Rescue of F508del-CFTR Using Small Molecule Correctors

Molinski, Steven; Eckford, Paul D. W.; Pasyk, Stan; Ahmadi, Saumel; Chin, Stephanie; Bear, Christine E.

doi:10.3389/fphar.2012.00160

Cited by 46 publications

(37 citation statements)

References 144 publications

(290 reference statements)

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“…Several small molecules called CFTR correctors have been shown to rescue the functional defect of ∆F508-CFTR by correcting its biosynthetic processing defect in cultured cells 11 - 13 , 25 . The present generation of CFTR correctors does not improve the decreased plasma membrane stability of r∆F508-CFTR and their clinical efficacy has been very limited in patients homozygous for the ∆F508 mutation 14 , 25 . Thus, we examined whether increasing stability of r∆F508-CFTR by silencing c-Cbl would complement the corrector effect on the functional defect of ∆F508-CFTR.…”

Section: Resultsmentioning

confidence: 99%

c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells

Cihil

Zimnik

Swiatecka‐Urban

2013

Communicative & Integrative Biology

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CFTR is a PKA activated Cl- channel expressed in the apical membrane of fluid transporting epithelia. We previously demonstrated that c-Cbl decreases CFTR stability in the plasma membrane by facilitating its endocytosis and lysosomal degradation in human airway epithelium. The most common mutation associated with cystic fibrosis, deletion of Phe508 (∆F508), leads to a temperature sensitive biosynthetic processing defect in the CFTR protein. Mature ∆F508-CFTR that has been rescued by low temperature or chemical chaperones is partially functional as a Cl- channel but has decreased plasma membrane stability due to altered post-maturational trafficking. Our present data demonstrate that c-Cbl controls the post-maturational trafficking of rescued ∆F508-CFTR. Partial depletion of c-Cbl increased stability of the plasma membrane associated mature ∆F508-CFTR and the ∆F508-CFTR mediated Cl- secretion. These data indicate that correcting the post-maturational trafficking of ∆F508-CFTR may represent a therapeutic approach complementary to the biosynthetic rescue. Because c-Cbl functions as an adaptor and scaffolding protein during CFTR endocytosis, we propose that interfering with the c-Cbl mediated endocytic recruitment of ∆F508-CFTR may increase stability of ∆508-CFTR in the plasma membrane after its biosynthetic rescue.

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Section: Resultsmentioning

confidence: 99%

c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells

Cihil

Zimnik

Swiatecka‐Urban

2013

Communicative & Integrative Biology

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“…We assessed functional restoration of F508del CFTR in cholangiocytes from CF-patient iPSCs by adding the chemical correctors VX-809 and Corr-4a to cultures 2 d before the CFTR functional assay [27][28][29][30] . Both molecules correct folding defects of mutant CFTR protein.…”

Section: Analyses Of Cholangiocytes Generated From Cf Patient Ipscsmentioning

confidence: 99%

Directed differentiation of cholangiocytes from human pluripotent stem cells

et al. 2015

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Although bile duct disorders are well-recognized causes of liver disease, the molecular and cellular events leading to biliary dysfunction are poorly understood. To enable modeling and drug discovery for biliary disease, we describe a protocol that achieves efficient differentiation of biliary epithelial cells (cholangiocytes) from human pluripotent stem cells (hPSCs) through delivery of developmentally relevant cues, including NOTCH signaling. Using three-dimensional culture, the protocol yields cystic and/or ductal structures that express mature biliary markers, including apical sodium-dependent bile acid transporter, secretin receptor, cilia and cystic fibrosis transmembrane conductance regulator (CFTR). We demonstrate that hPSC-derived cholangiocytes possess epithelial functions, including rhodamine efflux and CFTR-mediated fluid secretion. Furthermore, we show that functionally impaired hPSC-derived cholangiocytes from cystic fibrosis patients are rescued by CFTR correctors. These findings demonstrate that mature cholangiocytes can be differentiated from hPSCs and used for studies of biliary development and disease.

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“…Screening of chemical libraries has led to the identification of compounds that enhance function of this mutant chloride channel: those that boost processing and surface expression (referred to as correctors) and those that improve channel gating (referred to as potentiators) (19 -23). An emerging concept is that optimal functional restoration may be achieved through a combination of correctors and potentiators (24,25).…”

mentioning

confidence: 99%

Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism

Chen

Olson

Zhou

et al. 2013

Journal of Biological Chemistry

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Background: Defective folding and trafficking of ␤-cell ATP-sensitive potassium (K ATP ) channels causes congenital hyperinsulinism. Results: Carbamazepine improves the processing and surface expression of trafficking-impaired K ATP channels harboring a subset of sulfonylurea receptor 1 mutations. Conclusion: Carbamazepine is a novel corrector of K ATP channels. Significance: Carbamazepine may be used to treat congenital hyperinsulinism caused by defective K ATP channel trafficking.

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Functional Rescue of F508del-CFTR Using Small Molecule Correctors

Cited by 46 publications

References 144 publications

c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells

c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells

Directed differentiation of cholangiocytes from human pluripotent stem cells

Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism

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