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https://www.readbyqxmd.com/read/28930490/tezacaftor-ivacaftor-in-subjects-with-cystic-fibrosis-and-f508del-f508del-cftr-or-f508del-g551d-cftr
#1
Scott H Donaldson, Joseph M Pilewski, Matthias Griese, Jon Cooke, Lakshmi Viswanathan, Elizabeth Tullis, Jane C Davies, Julie A Lekstrom-Himes, Linda T Wang
RATIONALE: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES: To evaluate safety and efficacy of tezacaftor monotherapy and tezacaftor/ivacaftor combination therapy in subjects with CF homozygous for F508del or compound heterozygous for F508del and G551D...
September 20, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28925369/generation-of-a-gene-corrected-isogenic-control-ipsc-line-from-cystic-fibrosis-patient-specific-ipscs-homozygous-for-p-phe508del-mutation-mediated-by-talens-and-ssodn
#2
Sylvia Merkert, Christien Bednarski, Gudrun Göhring, Toni Cathomen, Ulrich Martin
Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which affects multiple organs. Human induced pluripotent stem cells (iPSCs) derived from CF patients and the generation of isogeneic gene-corrected control cell lines enable disease modelling, drug discovery or toxicological studies and therefore the development of CF patient-specific therapies. We have previously generated a hiPSC line from a CF patient homozygous for the p...
August 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28923049/roflumilast-reverses-cftr-mediated-ion-transport-dysfunction-in-cigarette-smoke-exposed-mice
#3
S Vamsee Raju, Lawrence Rasmussen, Peter A Sloane, Li Ping Tang, Emily Falk Libby, Steven M Rowe
BACKGROUND: Dysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) can be elicited by cigarette smoke and is observed in patients with chronic bronchitis. We have previously demonstrated in human airway epithelial cell monolayers that roflumilast, a clinically approved phosphodiesterase 4 inhibitor that reduces the risk of exacerbations in chronic obstructive pulmonary disease patients with chronic bronchitis and a history of exacerbations, activates CFTR-dependent chloride secretion via a cAMP-mediated pathway, partially restores the detrimental effects of cigarette smoke on CFTR-mediated ion transport, and increases CFTR-dependent gastrointestinal fluid secretion in isolated murine intestine segments...
September 18, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28918012/gene-editing-with-helper-dependent-adenovirus-can-efficiently-introduce-multiple-changes-simultaneously-over-a-large-genomic-region
#4
Donna J Palmer, Nathan C Grove, Dustin L Turner, Philip Ng
Helper-dependent adenoviral vectors (HDAds) possess long homology arms that mediate high-efficiency gene editing. These long homology arms may permit simultaneous introduction of multiple modifications into a large genomic region or may permit a single HDAd to correct many different individual mutations spread widely across a gene. We investigated this important potential using an HDAd bearing 13 genetic markers in the region of homology to the target CFTR locus in human iPSCs and found that all markers can be simultaneously introduced into the target locus, with the two farthest markers being 22...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28916704/delayed-neutrophil-apoptosis-enhances-net-formation-in-cystic-fibrosis
#5
Robert D Gray, Gareth Hardisty, Kate H Regan, Maeve Smith, Calum T Robb, Rodger Duffin, Annie Mackellar, Jennifer M Felton, Lily Paemka, Brian N McCullagh, Christopher D Lucas, David A Dorward, Edward F McKone, Gordon Cooke, Seamas C Donnelly, Pradeep K Singh, David A Stoltz, Christopher Haslett, Paul B McCray, Moira K B Whyte, Adriano G Rossi, Donald J Davidson
BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation...
September 15, 2017: Thorax
https://www.readbyqxmd.com/read/28916430/therapeutic-approaches-to-cftr-dysfunction-from-discovery-to-drug-development
#6
Hongyu Li, Emanuela Pesce, David N Sheppard, Ashvani K Singh, Nicoletta Pedemonte
Cystic fibrosis (CF) mutations have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. They disrupt its processing to and stability at the plasma membrane and function as an ATP-gated Cl(-) channel. Here, we review therapeutic strategies to overcome defective CFTR processing and stability. Because CF mutations have multiple impacts on the assembly of CFTR protein, combination therapy with several pharmacological chaperones is likely to be required to rescue mutant CFTR expression at the plasma membrane...
September 12, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28902888/dendrimer-based-selective-autophagy-induction-rescues-%C3%AE-f508-cftr-and-inhibits-pseudomonas-aeruginosa-infection-in-cystic-fibrosis
#7
Scott Mackenzie Brockman, Manish Bodas, David Silverberg, Ajit Sharma, Neeraj Vij
BACKGROUND: Cystic Fibrosis (CF) is a genetic disorder caused by mutation(s) in the CF-transmembrane conductance regulator (Cftr) gene. The most common mutation, ΔF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa), a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN)-based cysteamine analogue...
2017: PloS One
https://www.readbyqxmd.com/read/28900798/phenotypic-plasticity-in-gene-expression-and-physiological-response-in-red-drum-sciaenops-ocellatus-exposed-to-a-long-term-freshwater-environment
#8
Mariel Gullian Klanian, Omar Zapata Pérez, Miguel Angel Vela-Magaña
Red drum (Sciaenops ocellatus) is a euryhaline fish commonly found in the Gulf of Mexico and along the Atlantic coast of North America. Because of high commercial demand and its euryhaline characteristics, aquaculture of this species has diversified from marine to low-salinity aquaculture systems. In recent years, interest in the feasibility of producing red drum in inland freshwater systems has grown and this prompted us to investigate its osmoregulatory capacity after rearing for 8 months in a freshwater aquaculture system...
September 12, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/28898585/use-of-a-high-throughput-phenotypic-screening-strategy-to-identify-amplifiers-a-novel-pharmacological-class-of-small-molecules-that-exhibit-functional-synergy-with-potentiators-and-correctors
#9
Kenneth A Giuliano, Shinichiro Wachi, Lawrence Drew, Danijela Dukovski, Olivia Green, Cecilia Bastos, Matthew D Cullen, Sheila Hauck, Bradley D Tait, Benito Munoz, Po-Shun Lee, John Preston Miller
Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis...
September 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28891346/lumacaftor-ivacaftor-a-novel-agent-for-the-treatment-of-cystic-fibrosis-patients-who-are-homozygous-for-the-f580del-cftr-mutation
#10
Marilyn N Bulloch, Cameron Hanna, Richard Giovane
Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation...
September 11, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28888897/hepatobiliary-disease-in-children-and-adolescents-with-cystic-fibrosis
#11
Fernanda de S Nascimento, Nelson A Sena, Tatiane da A Ferreira, Cibele D F Marques, Luciana R Silva, Edna Lúcia S de Souza
OBJECTIVES: The aims of the study were to determine the frequency of hepatobiliary disease in patients with CF and to describe the sociodemographic, clinical, and laboratory profile of these patients. METHODS: This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with CF fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted, including sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies...
September 7, 2017: Jornal de Pediatria
https://www.readbyqxmd.com/read/28887112/protein-and-lipid-interactions-modulating-cftr-trafficking-and-rescue
#12
Carlos M Farinha, Elizabeth Miller, Nael McCarty
Different levels of CFTR regulation in the cell contribute to a stringent control of chloride secretion in epithelia. Tuning of chloride transport is achieved by modulating CFTR biogenesis, exit from the endoplasmic reticulum, trafficking, membrane stability and channel activity. In this short review, we summarize recent findings identifying interactions with other proteins - directly or through membrane lipids - and briefly discuss how these observations can provide clues to the design of better therapeutic approaches...
September 5, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28883468/ezrin-links-cftr-to-tlr4-signaling-to-orchestrate-anti-bacterial-immune-response-in-macrophages
#13
Caterina Di Pietro, Ping-Xia Zhang, Timothy K O'Rourke, Thomas S Murray, Lin Wang, Clemente J Britto, Jonathan L Koff, Diane S Krause, Marie E Egan, Emanuela M Bruscia
Macrophages (MΦs) with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) have blunted induction of PI3K/AKT signaling in response to TLR4 activation, leading to hyperinflammation, a hallmark of cystic fibrosis (CF) disease. Here, we show that Ezrin links CFTR and TLR4 signaling, and is necessary for PI3K/AKT signaling induction in response to MΦ activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MΦs are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MΦs...
September 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881097/toward-inclusive-therapy-with-cftr-modulators-progress-and-challenges
#14
Jennifer Guimbellot, Jyoti Sharma, Steven M Rowe
Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established...
September 7, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28878137/cf-airway-smooth-muscle-transcriptome-reveals-a-role-for-pyk2
#15
Daniel P Cook, Ryan J Adam, Keyan Zarei, Benjamin Deonovic, Mallory R Stroik, Nicholas D Gansemer, David K Meyerholz, Kin Fai Au, David A Stoltz
Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28877849/not-all-is-cftr-neutrophils-and-cholesterol-in-cystic-fibrosis
#16
Stefano Castellani, Massimo Conese
No abstract text is available yet for this article.
September 1, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28875346/cftr-supports-cell-death-through-ros-dependent-activation-of-tmem16f-anoctamin-6
#17
Filipa Simões, Jiraporn Ousingsawat, Podchanart Wanitchakool, Ana Fonseca, Inês Cabrita, Roberta Benedetto, Rainer Schreiber, Karl Kunzelmann
Cystic fibrosis transmembrane conductance regulator (CFTR) is the essential chloride and bicarbonate channel in the apical membrane of epithelial cells. CFTR was also proposed earlier to conduct glutathione (GSH) out of airway epithelial cells to be enriched in the apical airway surface liquid to neutralize reactive oxygen species (ROS). Although earlier studies suggested that release of GSH by wild type (wt) CFTR may lead to an increase in cytosolic ROS, we did not detect different ROS levels in cells expressing wt-CFTR and mutant F508del-CFTR, independent of CFTR-activation or exposure to the ROS donor tert-butyl hydroperoxide...
September 5, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28874823/role-of-smad3-and-p38-signalling-in-cigarette-smoke-induced-cftr-and-bk-dysfunction-in-primary-human-bronchial-airway-epithelial-cells
#18
Juliette Sailland, Astrid Grosche, Nathalie Baumlin, John S Dennis, Andreas Schmid, Stefanie Krick, Matthias Salathe
Mucociliary clearance (MCC) is a major airway host defence system that is impaired in patients with smoking-associated chronic bronchitis. This dysfunction is partially related to a decrease of airway surface liquid (ASL) volume that is in part regulated by apically expressed cystic fibrosis transmembrane conductance regulator (CFTR) and large-conductance, Ca(2+)-activated, and voltage dependent K(+) (BK) channels. Here, data from human bronchial epithelial cells (HBEC) confirm that cigarette smoke not only downregulates CFTR activity but also inhibits BK channel function, thereby causing ASL depletion...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28873176/pro-secretory-activity-and-pharmacology-in-rabbits-of-an-aminophenyl-1-3-5-triazine-cftr-activator-for-dry-eye-disorders
#19
Christian M Felix, Sujin Lee, Marc H Levin, Alan S Verkman
Purpose: Pharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits...
September 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28869532/cftr-nherf2-lpa%C3%A2-complex-in-the-airway-and-gut-epithelia
#20
REVIEW
Weiqiang Zhang, Zhihong Zhang, Yanhui Zhang, Anjaparavanda P Naren
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl(-)) and bicarbonate (HCO₃(-)) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with altered CFTR channel function. Cystic fibrosis (CF) is caused by the absence or dysfunction of CFTR channel activity, resulting from mutations in the gene...
September 4, 2017: International Journal of Molecular Sciences
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