Identification of 99% of CFTR gene mutations in Bulgarian-, Bulgarian Turk-, and Roma cystic fibrosis patients. Establishing efficacy using in vitro data in lieu of a clinical trial, Physiological and pharmacological characterization of the N1303K mutant CFTR, Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators, Measurements of functional responses in human primary lung cells as a basis for personalized therapy for cystic fibrosis, Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action, Decreased mRNA and protein stability of W1282X limits response to modulator therapy, Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells, CFTR: New insights into structure and function and implications for modulation by small molecules, Unravelling the regions of mutant F508del-CFTR more susceptible to the action of four cystic fibrosis correctors, Insights into the variability of nasal potential difference, a biomarker of CFTR activity, Predictive factors for lumacaftor/ivacaftor clinical response, Utilizing centralized biorepository samples for biomarkers of cystic fibrosis lung disease severity, Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries, Answering the call to address cystic fibrosis treatment burden in the era of highly effective CFTR modulator therapy, Improving outcomes of infections in cystic fibrosis in the era of CFTR modulator therapy, Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells, Quorum sensing down-regulation counteracts the negative impact of Pseudomonas aeruginosa on CFTR channel expression, function and rescue in human airway epithelial cells, Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease, The phenotypic consequences of CFTR mutations, Cystic fibrosis liver disease: Outcomes and risk factors in a large cohort of French patients, Genetic modifiers of cystic fibrosis-related diabetes have extensive overlap with type 2 diabetes and related traits, Sustained glycemic control with ivacaftor in cystic fibrosis-related diabetes, Islet hormone and incretin secretion in cystic fibrosis after four months of ivacaftor therapy, In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis, Evaluation of CV risk in a lung cancer screening cohort, Bioartificial lungs using de- and recellularisation approaches, Using a molecular classifier to identify UIP in TBLB samples, http://creativecommons.org/licenses/by-nc/4.0/. NLM Industry partners began high throughput screening for CFTR modulators. This last decade has created historical moments for CF, primarily driven by the development of CFTR modulators. Why this difference? Over the past decade, CFTR protein modulators have been developed, which improve CFTR function either through potentiation of the abnormal protein channel at the cell surface (eg, ivacaftor) or through correction of protein transport to the cell surface (eg, lumacaftor and tezacaftor); these treatments have now been approved by the European Medicines Agency and US Food and Drug Administration for use in people with cystic fibrosis … It has been demonstrated that in-vitro exposure of Pseudomonas aeruginosa (P. aeruginosa) reduced Orkambi-mediated rescue of CFTR function in human bronchial epithelial cells and stimulated the expression of pro-inflammatory cytokines (IL-6 and IL-8) [52, 53]. These drugs demonstrate disease modulation by decreasing pulmonary exacerbations as well as lung function decline, a correlate of survival [ 1 Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. Epub 2019 Jun 27. Conflict of interest: O. Laselva has nothing to disclose. This patient-to-patient variability has been represented in vitro using patient samples, where it was observed that patient responses to lumacaftor or Orkambi can largely vary even among people carrying the same CFTR mutation [25–27]. The three main types of modulators are potentiators, correctors, and amplifiers. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Drugs that target the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein are called CFTR modulators. Sign In to Email Alerts with your Email Address, The era of CFTR modulators: improvements made and remaining challenges, Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA, Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR), cAMP-regulated whole cell chloride currents in pancreatic duct cells, Functional rescue of F508del-CFTR using small molecule correctors, Tezacaftor and ivacaftor for the treatment of cystic fibrosis, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function, Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, Molecular mechanism of action of trimethylangelicin derivatives as CFTR modulators, Corrector VX-809 stabilizes the first transmembrane domain of CFTR, Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis, Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele, Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial, Elexacaftor/ivacaftor/tezacaftor: First approval, VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface, Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis, Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators, The influence of CFTR complex alleles on precision therapy of cystic fibrosis, Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity, The genetics and genomics of cystic fibrosis, Females with cystic fibrosis demonstrate a differential response profile to ivacaftor compared to males, Human primary epithelial cell models: Promising tools in the era of cystic fibrosis personalized medicine, The CF Canada-Sick Kids program in individual CF therapy: A resource for the advancement of personalized medicine in CF, Rectal organoids enable personalized treatment of cystic fibrosis, CFTR modulator theratyping: Current status, gaps and future directions, Cystic fibrosis precision therapeutics: Emerging considerations, The U.S. Food and Drug Administration's experience with ivacaftor in cystic fibrosis. Ann Pharmacother. The triple CFTR modulation therapy demonstrated good tolerability with only mild or moderate adverse effects and very low rate of discontinuation [20, 21]. CFTR modulators are an exciting new class of drugs that treat the underlying defect with small molecules that either improve intracellular trafficking or activates the defective CFTR channel. Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. In this review, we discuss issues regarding drug interactions, organ transplantation and CFTR modulation. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Pediatr Clin North Am. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Experts in the CF field still maintain that “structural biology and functional studies are a powerful combination to elucidate fundamental knowledge about CFTR and are key for the development of better drugs to enable people with CF to live full and active lives” [44, 45]. Symdeko was approved, alongside F508del, for a large number of “residual function” CFTR mutations based on in vitro culture responses, paving the way for the triple CFTR modulation [7]. Sep 7, 2020 The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Cystic fibrosis is caused by a faulty gene that affects the production of a protein called CFTR. Author information: (1)West Midlands Adult Cystic Fibrosis Centre, University Hospitals Birmingham NHS Foundation Trust, Bordesley Green East, Birmingham, United Kingdom. The clinical introduction of CFTR modulators, which are able to restore some CFTR function, has significantly improved the disease course of CF patients over the past years. Mayer-Hamblett N, Boyle M, VanDevanter D. Thorax. Even in the era of CFTR modulation therapies, the detection, diagnosis, and treatment of some CF micro-organisms remains challenging, especially for patients with more advanced stages of lung disease [51]. Clipboard, Search History, and several other advanced features are temporarily unavailable. On the other hand, it has been recently demonstrated that a combination of CFTR modulators alongside a small molecule that inhibits the nonsense-mediated RNA decay can rescue the functional expression of W1282X-CFTR in heterologous systems and primary nasal epithelial cells [41–43]. | Research efforts to evaluate the clinical effectiveness and impact on infections is ongoing in future triple-combination CFTR modulator therapy studies [51]. Kalydeco (ivacaftor) is a CFTR potentiator developed by Vertex Pharmaceuticals. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis. Epub 2012 Jun 26. • S 19 : Dilemmas in CFTR modulators • S 25 : Novel clinical outcome measures in pre-school children with cystic fibrosis • S 29 : What’s influencing adherence ? Conflict of interest: J. Avolio has nothing to disclose. Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators represent a paradigm shift in the treatment landscape of CF ().The effects of CFTR modulators on respiratory function, pulmonary exacerbations, and quality of life have been well documented, as these important clinical endpoints form the basis for regulatory agency approval (). Thus, in addition to focusing on the lung disease paradigm, clinical measures to predict the effect of new CFTR modulators on other CF related symptoms [59, 60] and even on establishing organ function early in life [61] are needed. Potentiators and correctors. CFTR modulators; Cystic fibrosis; Drug interactions; Organ transplantation. 2020 Jul;34(4):573-580. doi: 10.1177/1945892420912368. PBMCs … Epub 2020 Mar 13. In this study, although treatment with lumacaftor/ivacaftor reduced exacerbations, the unacceptably frequent adverse events resulted in a very high discontinuation rate [55]. The identification of reliable individual response prediction tools is even more important for those patients carrying refractory CFTR variants not addressed by available modulators and for those who carry extremely rare CFTR mutations [35–37]. These CFTR modulators are each approved for specific mutations and age groups. Overall the triple-combination, elexacaftor, tezacaftor, and ivacaftor (marketed as Trikafta, Vertex Pharmaceuticals), demonstrated statistically significant and/or clinically meaningful improvements in lung function (10–14% of FEV1 % pred) and respiratory-related quality of life for patients with one copy of the F508del mutation and a minimal-function mutation and patients with two F508del copies [20, 21]. There are more than 1900 different variants of the CFTR gene, but most people with CF (over 90% in the UK) have at least one copy of the faulty F508del gene. Airway Inflammation and Host Responses in the Era of CFTR Modulators. 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