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https://www.readbyqxmd.com/read/27895116/correctors-and-potentiators-rescue-function-of-the-truncated-w1282x-cftr-translation-product
#1
Peter M Haggie, Puay-Wah Phuan, Joseph-Anthony Tan, Haijin Xu, Radu G Avramescu, Doranda Perdomo, Lorna Zlock, Dennis W Nielson, Walter E Finkbeiner, Gergely L Lukacs, Alan S Verkman
W1282X is the fifth most common CFTR mutation that causes cystic fibrosis. Here, we investigated the utility of a small molecule corrector / potentiator strategy, as used for ΔF508-CFTR, to produce functional rescue of the truncated translation product of the W1282X mutation, CFTR1281, without the need for read-through. In transfected cell systems, certain potentiators and correctors including VX-809 and VX-770 increased CFTR1281 activity. To identify novel correctors and potentiators with potentially greater efficacy on CFTR1281, functional screens were done of ~30,000 synthetic small molecules and drugs/nutraceuticals in CFTR1281-transfected cells...
November 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27614011/the-investigational-cystic-fibrosis-drug-trimethylangelicin-directly-modulates-cftr-by-stabilizing-the-first-membrane-spanning-domain
#2
Onofrio Laselva, Steven Molinski, Valeria Casavola, Christine E Bear
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, deletion of phenylalanine 508 (F508del), disrupts tertiary assembly, causing protein misprocessing and loss of CFTR function in epithelial tissues. Lumacaftor (VX-809) is a Class 1 corrector molecule shown to partially rescue misprocessing of F508del and together with the potentiator of channel activity: ivacaftor (VX-770) has been approved for treatment of CF patients homozygous for the F508del mutation...
November 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27571970/generation-of-%C3%AE-f508-cftr-t84-cell-lines-by-crispr-cas9-mediated-genome-editing
#3
Woo Young Chung, Myungjae Song, Jinhong Park, Wan Namkung, Jinu Lee, Hyongbum Kim, Min Goo Lee, Joo Young Kim
OBJECTIVES: To provide a simple method to make a stable ΔF508-CFTR-expressing T84 cell line that can be used as an efficient screening model system for ΔF508-CFTR rescue. RESULTS: CFTR knockout cell lines were generated by Cas9 with a single-guide RNA (sgRNA) targeting exon 1 of the CFTR genome, which produced indels that abolished CFTR protein expressions. Next, stable ΔF508-CFTR expression was achieved by genome integration of ΔF508-CFTR via the lentivirus infection system...
August 29, 2016: Biotechnology Letters
https://www.readbyqxmd.com/read/27402691/restoration-of-r117h-cftr-folding-and-function-in-human-airway-cells-through-combination-treatment-with-vx-809-and-vx-770
#4
Martina Gentzsch, Hong Y Ren, Scott A Houck, Nancy L Quinney, Deborah M Cholon, Pattarawut Sopha, Imron G Chaudhry, Jhuma Das, Nikolay V Dokholyan, Scott H Randell, Douglas M Cyr
Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations...
September 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27334259/characterizing-responses-to-cftr-modulating-drugs-using-rectal-organoids-derived-from-subjects-with-cystic-fibrosis
#5
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27298017/efficacy-and-safety-of-lumacaftor-ivacaftor-combination-therapy-in-patients-with-cystic-fibrosis-homozygous-for-phe508del-cftr-by-pulmonary-function-subgroup-a-pooled-analysis
#6
J Stuart Elborn, Bonnie W Ramsey, Michael P Boyle, Michael W Konstan, Xiaohong Huang, Gautham Marigowda, David Waltz, Claire E Wainwright
BACKGROUND: Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. METHODS: Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies...
August 2016: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/27214033/mechanistic-approaches-to-improve-correction-of-the-most-common-disease-causing-mutation-in-cystic-fibrosis
#7
Vedrana Bali, Ahmed Lazrak, Purushotham Guroji, Sadis Matalon, Zsuzsanna Bebok
The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single "corrector". Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function...
2016: PloS One
https://www.readbyqxmd.com/read/27168400/ribosomal-stalk-protein-silencing-partially-corrects-the-%C3%AE-f508-cftr-functional-expression-defect
#8
Guido Veit, Kathryn Oliver, Pirjo M Apaja, Doranda Perdomo, Aurélien Bidaud-Meynard, Sheng-Ting Lin, Jingyu Guo, Mert Icyuz, Eric J Sorscher, John L Hartman Iv, Gergely L Lukacs
The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects...
May 2016: PLoS Biology
https://www.readbyqxmd.com/read/27160424/potentiator-synergy-in-rectal-organoids-carrying-s1251n-g551d-or-f508del-cftr-mutations
#9
Johanna F Dekkers, Peter Van Mourik, Annelotte M Vonk, Evelien Kruisselbrink, Gitte Berkers, Karin M de Winter-de Groot, Hettie M Janssens, Inez Bronsveld, Cornelis K van der Ent, Hugo R de Jonge, Jeffrey M Beekman
The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities...
September 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27146408/characterization-of-mitochondrial-function-in-cells-with-impaired-cystic-fibrosis-transmembrane-conductance-regulator-cftr-function
#10
Anna Atlante, Maria Favia, Antonella Bobba, Lorenzo Guerra, Valeria Casavola, Stephan Joel Reshkin
Evidence supporting the occurrence of oxidative stress in Cystic Fibrosis (CF) is well established and the literature suggests that oxidative stress is inseparably linked to mitochondrial dysfunction. Here, we have characterized mitochondrial function, in particular as it regards the steps of oxidative phosphorylation and ROS production, in airway cells either homozygous for the F508del-CFTR allele or stably expressing wt-CFTR. We find that oxygen consumption, ΔΨ generation, adenine nucleotide translocator-dependent ADP/ATP exchange and both mitochondrial Complex I and IV activities are impaired in CF cells, while both mitochondrial ROS production and membrane lipid peroxidation increase...
June 2016: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/27103391/optimal-correction-of-distinct-cftr-folding-mutants-in-rectal-cystic-fibrosis-organoids
#11
Johanna F Dekkers, Ricardo A Gogorza Gondra, Evelien Kruisselbrink, Annelotte M Vonk, Hettie M Janssens, Karin M de Winter-de Groot, Cornelis K van der Ent, Jeffrey M Beekman
Small-molecule therapies that restore defects in cystic fibrosis transmembrane conductance regulator (CFTR) gating (potentiators) or trafficking (correctors) are being developed for cystic fibrosis (CF) in a mutation-specific fashion. Options for pharmacological correction of CFTR-p.Phe508del (F508del) are being extensively studied but correction of other trafficking mutants that may also benefit from corrector treatment remains largely unknown.We studied correction of the folding mutants CFTR-p.Phe508del, -p...
August 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/26863533/potentiation-of-%C3%AE-f508-and-g551d-cftr-mediated-cl-current-by-novel-hydroxypyrazolines
#12
Jinhong Park, Poonam Khloya, Yohan Seo, Satish Kumar, Ho K Lee, Dong-Kyu Jeon, Sungwoo Jo, Pawan K Sharma, Wan Namkung
The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique...
2016: PloS One
https://www.readbyqxmd.com/read/26823603/correctors-of-mutant-cftr-enhance-subcortical-camp-pka-signaling-through-modulating-ezrin-phosphorylation-and-cytoskeleton-organization
#13
Anna C Abbattiscianni, Maria Favia, Maria T Mancini, Rosa A Cardone, Lorenzo Guerra, Stefania Monterisi, Stefano Castellani, Onofrio Laselva, Francesca Di Sole, Massimo Conese, Manuela Zaccolo, Valeria Casavola
The most common mutation of the cystic fibrosis transmembrane regulator (CFTR) gene, F508del, produces a misfolded protein resulting in its defective trafficking to the cell surface and an impaired chloride secretion. Pharmacological treatments partially rescue F508del CFTR activity either directly by interacting with the mutant protein and/or indirectly by altering the cellular protein homeostasis. Here, we show that the phosphorylation of ezrin together with its binding to phosphatidylinositol-4,5-bisphosphate (PIP2) tethers the F508del CFTR to the actin cytoskeleton, stabilizing it on the apical membrane and rescuing the sub-membrane compartmentalization of cAMP and activated PKA...
March 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26800689/c-3623g%C3%A2-%C3%A2-a-mutation-encodes-a-cftr-protein-with-impaired-channel-function
#14
Xiaoying Zhang, Jaspal S Hothi, Yanhui H Zhang, Saumini Srinivasan, Dennis C Stokes, Weiqiang Zhang
BACKGROUND: The aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation. METHODS: The medical record of this patient was analyzed retrospectively. Western blotting and iodide efflux assay were used to study mutant CFTR protein expression level, maturation status, channel function, and the effects of CFTR modulation on these characteristics...
2016: Respiratory Research
https://www.readbyqxmd.com/read/26701662/phenylhydrazones-as-correctors-of-a-mutant-cystic-fibrosis-transmembrane-conductance-regulator
#15
Erika Nieddu, Benedetta Pollarolo, Marco T Mazzei, Maria Anzaldi, Silvia Schenone, Nicoletta Pedemonte, Luis J V Galietta, Mauro Mazzei
The phenylhydrazone RDR-1 is endowed with moderate activity as F508del-CFTR corrector; nevertheless, its simple structure enables stimulating developments in this class of correctors. Therefore, we synthesized a number of phenylhydrazones 3 by reacting phenylhydrazine derivatives 1 with furfural derivatives 2. By the same reaction, also the pyridine derivatives 4, the thiophene derivatives 5, and the hydrazides 6 and 7 were prepared. All compounds were tested as F508del-CFTR correctors in the cystic fibrosis (CF) bronchial epithelial cell line CFBE41o-, using corr-4a and VX-809 as controls...
February 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/26648081/pharmacological-correction-of-cystic-fibrosis-molecular-mechanisms-at-the-plasma-membrane-to-augment-mutant-cftr-function
#16
REVIEW
Kavisha Arora, Anjaparavanda P Naren
In the late 1980s, a loss-of-function mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel was identified to be the primary cause of cystic fibrosis (CF); a fatal multiple-organ disorder that mostly affects Caucasians. To date, approximately 2000 genetic mutations have been identified in the CFTR gene (http://www.genet.sickkids.on.ca/cftr/app). The most common cause of morbidity and mortality in persons with CF is a progressive deterioration in lung function leading ultimately to respiratory collapse...
2016: Current Drug Targets
https://www.readbyqxmd.com/read/26515683/cftr-regulated-mapk-nf-%C3%AE%C2%BAb-signaling-in-pulmonary-inflammation-in-thermal-inhalation-injury
#17
Zhi Wei Dong, Jing Chen, Ye Chun Ruan, Tao Zhou, Yu Chen, YaJie Chen, Lai Ling Tsang, Hsiao Chang Chan, Yi Zhi Peng
The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26492939/low-free-drug-concentration-prevents-inhibition-of-f508del-cftr-functional-expression-by-the-potentiator-vx-770-ivacaftor
#18
Elizabeth Matthes, Julie Goepp, Graeme W Carlile, Yishan Luo, Kurt Dejgaard, Arnaud Billet, Renaud Robert, David Y Thomas, John W Hanrahan
BACKGROUND AND PURPOSE: The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. EXPERIMENTAL APPROACH: CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination...
February 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26336913/a-synonymous-codon-change-alters-the-drug-sensitivity-of-%C3%AE-f508-cystic-fibrosis-transmembrane-conductance-regulator
#19
Vedrana Bali, Ahmed Lazrak, Purushotham Guroji, Lianwu Fu, Sadis Matalon, Zsuzsanna Bebok
Synonymous mutations, such as I507-ATC→ATT, in deletion of Phe508 in cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR), the most frequent disease-associated mutant of CFTR, may affect protein biogenesis, structure, and function and contribute to an altered disease phenotype. Small-molecule drugs are being developed to correct ΔF508 CFTR. To understand correction mechanisms and the consequences of synonymous mutations, we analyzed the effect of mechanistically distinct correctors, corrector 4a (C4) and lumacaftor (VX-809), on I507-ATT and I507-ATC ΔF508 CFTR biogenesis and function...
January 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/26245207/potentiators-of-defective-%C3%AE-f508-cftr-gating-that-do-not-interfere-with-corrector-action
#20
Puay-Wah Phuan, Guido Veit, Joseph A Tan, Walter E Finkbeiner, Gergely L Lukacs, A S Verkman
Combination drug therapies under development for cystic fibrosis caused by the ∆F508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) include a "corrector" to improve its cellular processing and a "potentiator" to improve its chloride channel function. Recently, it was reported that the approved potentiator N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Ivacaftor) reduces ∆F508-CFTR cellular stability and the efficacy of investigational correctors, including 3-(6-[([1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl) amino]-3-methyl-2-pyridinyl)-benzoic acid and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl), which might contribute to the modest reported efficacy of combination therapy in clinical trials...
October 2015: Molecular Pharmacology
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