Potentiators and correctors. Symdeko was associated with a significantly lower frequency of pulmonary exacerbations and improvement of FEV1 % pred (3.4% mean) compared to baseline, although no significant differences were observed in BMI. More than 2000 CF-causing mutations have been identified [4, 5]. 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 … Therefore, in order to better tailor personalised treatment choices, new research directions need to identify reliable in vitro systems to predict individual patient responses [32–35]. Am J Respir Crit Care Med. Loop diuretics are inhibitors ofNa+-K+-2Cr-cotranspOlter isofOlm 1 (NKCC1) located in the basolateral membrane of epithelial cells. 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. Until the last decade, the only available treatments for CF were focused on managing the symptoms of the disease. Its production is affected by different mutations. Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1]. Moreover, at trial completion, participants were given the option to enrol in a 96-week open-label extension trial. Thus, these treatments that target the underlying cause of CF have the potential to change the course of CF clinical disease [7, 8]. CFTR modulators currently in the clinic The clinical introduction of CFTR modulators, which are able to restore some CFTR function, has significantly improved … 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. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Review for the Otolaryngologist. doi: 10.1002/mgg3.696. Ann Pharmacother. USA.gov. Lumacaftor is a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) and ivacaftor is a potentiator of the CFTR. Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations. Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. Differences have also been described between the response observed in females and males under treatment with ivacaftor [31]. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Please enable it to take advantage of the complete set of features! Epub 2019 Jun 27. Although the triple-combination therapy achieved an improvement in patients homozygous for F508del much higher than previous CFTR modulators, reaching levels comparable to the benefit of ivacaftor for G551D patients, the benefit observed for patients with only one F508del copy involved more profound significance for the CF treatment paradigm of these patients. Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. Am J Rhinol Allergy. CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes AlexanderJ.Currie1,2,EllenT.Main 1,HeatherM.Wilson ,DariusArmstrong-James3 and AdiliaWarris2* 1AberdeenFungalGroup,InstituteofMedicalSciences,UniversityofAberdeen,Aberdeen,UnitedKingdom,2Medical CFTR modulators are the first pharmaceutical class designed specifically to alter the basic defect in CF by either improving the function of CFTR protein present at the cell surface and/or improving the tra cking of the CFTR to the cell surface [20,21]. JAMA. The results of these phase 3 clinical studies were similar for the F508del–minimal function and F508 homozygous patients, showing an improvement of FEV1 % pred (in the range of 10.4–13.8%) compared to the control [20] or actively-controlled patients [21], reduction of the sweat chloride concentration (−39.1 to −43.4) and higher patient-reported quality of life. In addition, even with these novel drug therapies, managing infections will continue to be a challenge, thus the CF community will need to adapt the standards for an improving, but ageing CF population. • 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 ? 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.  |  These drugs demonstrate disease modulation by decreasing pulmonary exacerbations as well as lung function decline, a correlate of survival [ 1 Epub 2016 Feb 22. As a recent study identified, in these cases, the goal would be to study the effects of withdrawing one or more chronic treatments to reduce the CF treatment burden [50]. Driving causes proposed for this variability [28] as well as disease severity [29] have been the genetic variants within and outside the CFTR locus [30]. 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/. 2017 Dec 5;318(21):2130-2131. doi: 10.1001/jama.2017.16823. 2 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06510, USA. The entry into the clinic of CFTR modulators such as TRIKAFTA has significantly improved life for ∼90% CF patients carrying one or two F508del mutations but challenges remain for rare CFTR mutations and the management of lung infections @SaraOcana1 https://bit.ly/3aRafQF. In contrast to non-responding patients, there are many people with CF experiencing a great benefit under the mentioned CFTR modulator therapies [49]. The three main types of modulators are potentiators, correctors, and amplifiers. Furthermore, it remains to be determined whether the next generation of modulators will be effective for individuals bearing rare mutations that are Orkambi resistant. In this study, although treatment with lumacaftor/ivacaftor reduced exacerbations, the unacceptably frequent adverse events resulted in a very high discontinuation rate [55]. The most common mutation, the deletion of phenylalanine at position 508 (F508del), induces misfolding of the protein that is retained in the endoplasmic reticulum and degraded by proteasomal pathways [6]. Conflict of interest: J. Avolio has nothing to disclose. A defective CFTR protein produces an impaired ion and fluid secretion in the epithelial cells affecting several organs and leading to severe lung disease. Currently these drugs are confined to people with a limited selection of genetic mutations. HHS 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]. The CFTR protein is an ion channel that mediates chloride and bicarbonate transport in epithelial cells of multiple organs including lungs, pancreas and intestine [2, 3]. Phenotyping Ciliary Dynamics and Coordination in Response to CFTR-modulators in Cystic Fibrosis Respiratory Epithelial Cells M Chioccioli ... 1 Biological and Soft Systems Sector, Cavendish Laboratory, University of Cambridge, Cambridge, CB3 0HE, UK. However, CFTR mutations can lead to theproduction of defective proteins or to producing no protein at all. CFTR modulators are currently considered contraindicated in patients with a solid organ transplant. CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Ivacaftor, a potentiator, increases the time that the CFTR chloride channel remains open. However, long-term treatment (24–48 h) of lumacaftor in combination with ivacaftor in vitro diminishes the pharmacological correction of F508del-CFTR [16, 17]. In this review, we discuss issues regarding drug interactions, organ transplantation and CFTR modulation. CF arises due to mutational dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Mayer-Hamblett N, Boyle M, VanDevanter D. Thorax. Cystic fibrosis is caused by a faulty gene that affects the production of a protein called CFTR. After 24 weeks of treatment with Orkambi, patients homozygous for F508del experienced a reduction in the rate of pulmonary exacerbations (30–39%), an absolute change in body mass index (BMI, 0.13–0.41) and an increment of percentage of predicted forced expiratory volume in 1 s (FEV1 % pred) between 4.3% and 6.7% [13]. NLM This excludes many patients who may benefit from the multisystem effects of CFTR modulator treatment. Conflict of interest: R. Nenna has nothing to disclose. Industry partners began high throughput screening for CFTR modulators. Patients with CFhave mutations in the CFTR gene, which is supposed to create a protein thatregulates the flow of water and chloride in and out of the cells that line thelungs, pancreas, and other organs. Petrova G, Yaneva N, Hrbková J, Libik M, Savov A, Macek M Jr. Mol Genet Genomic Med. However, treatment with antibiotic tobramycin and antimicrobial peptide, has been shown to restore Orkambi-mediated rescue of F508del-CFTR function in human bronchial epithelial cells infected with clinical strains of P. aeruginosa [54]. However, accumulating evidence from previous CFTR modulators prescriptions suggest that not all the patients who are predicted to respond to these treatments might experience the expected benefit. 2012 Jul-Aug;46(7-8):1065-75. doi: 10.1345/aph.1R076. However, the effectiveness of the same CFTR modulator combination therapy to rescue the processing defect for other rare CFTR mutations remains to be determined. New modulators are in development which will lead to the majority of patients with CF becoming eligible for treatment.  |  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. CFTR modulators have been developed as a targeted strategy to restore CFTR function in specific CFTR mutation types. It may be foreseeable that additional therapies or changes to standard of care are needed for these patients, in hopes of changing the scenario from a life-shortening disease to a treatable chronic condition. CFTR modulators; Cystic fibrosis; Drug interactions; Organ transplantation. SPEEDING UP ACCESS TO NEW DRUGS FOR CYSTIC FIBROSIS: CONSIDERATIONS FOR CLINICAL TRIAL DESIGN AND DELIVERY. But in UK, CF patients still don’t have access to Orkambi 3.5 years after American FDA approval (aside from severe cases in the UK – in 2017 243 patients received the drug). This site needs JavaScript to work properly. CFTR modulators increase the phagocytic capacity in CF macrophages, alter CF macrophage cytokine production, and alter CF monocyte activation 27, 50, 51. eCollection 2019 Apr. … This was followed by phase 2 clinical studies where a triple combination of CFTR modulators was tested in patients who were heterozygous for the F508del CFTR mutation and a minimal-function mutation (F508del–minimal function genotype), demonstrating improvements in CFTR function and clinical outcomes. CFTR transports anions, including chloride and bicarbonate, across the epithelial cell membrane through a cAMP regulated channel, and reduction in this function leads to ion imbalance and dehydration of the epithelial surface [ 1 Advancing clinical development pathways for new CFTR modulators in cystic fibrosis. Ivacaftor is a CFTR potentiator that improves channel opening and is commissioned in the UK for patients with gating mutations, most commonly G551D. Epub 2020 Mar 13. 2019 Aug;7(8):e696. In addition to the lung disease symptoms, CF usually affects pancreas, liver and digestive system, often leading to pancreatic insufficiency, CF-related diabetes, CF liver disease, severe malabsorption and meconium ileus [56–58]. It has been demonstrated that Orkambi showed a modest response to some of these rare mutations (A455E, M1101K, N1303K) in heterologous expression systems [38, 39]. CFTR correctors are pharmacological compounds that rescue the CFTR protein to the cell surface. Clin Case Rep. 2019 Feb 17;7(4):616-618. doi: 10.1002/ccr3.2053. These encouraging results led to the first phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial where the triple-combination, elexacaftor, tezacaftor, and ivacaftor, was randomised versus placebo for 403 patients with F508del–minimal function genotypes for 24 weeks [20]. Lee SE, Farzal Z, Daniels MLA, Thorp BD, Zanation AM, Senior BA, Ebert CS Jr, Kimple AJ. Today’s article is the first in a two-part series discussing to CFTR modulators. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. The cystic fibrosis community has access to three cystic fibrosis transmembrane conductance regulator (CFTR) modulators right now: Kalydeco (ivacaftor), Orkambi (lumacaftor /ivacaftor), and Symdeko (tezacaftor/ivacaftor). COVID-19 is an emerging, rapidly evolving situation. Keywords: 2016 May;71(5):454-61. doi: 10.1136/thoraxjnl-2015-208123. Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, Wege S, Mairbäurl H, Dorda M, Hyde R, Bagheri-Hanson A, Rueckes-Nilges C, Fischer S, Mall MA, Tümmler B. Finally, as the median survival for CF continues to increase and the CF population ages, new models for CF care will need to be adopted to tackle an increasing CF population with both CF morbidities and additional diseases of ageing [8]. 2016 Aug;63(4):751-64. doi: 10.1016/j.pcl.2016.04.006. 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]. Treating Specific Variants Causing Cystic Fibrosis. The Cystic Fibrosis Foundation has put forth efforts through the Infection Research Initiative to tackle these issues, including the development of new anti-infective therapies. However, this correction was not recapitulated in patient-derived tissues [40]. In the present study we reviewed the CFTR modulators currently in the clinic, the improvements made as well as the challenges that still need to be overcome in the field of CF treatments. Authors: On behalf of the European CF Society (ECFS) Strategic Planning Task Force on ‘Speeding up access to new drugs for CF’: Margarida Amaral6, Kris de Boeck7, Jane C Davies1, […] Read more. In addition to CFTR-directed modulators, CFTR dysfunction might be compensated by targeting alternative ion channels, such as ENaC (Moore and Tarran, 2018), the calcium-activated chloride channel transmembrane protein membrane 16A (TMEM16A) (Sondo et al., 2014), and the solute carrier 26A9 (SLC26A9) (Balázs and Mall, 2018). Enter multiple addresses on separate lines or separate them with commas. 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]. This last decade has created historical moments for CF, primarily driven by the development of CFTR modulators. CFTR modulators, which treat the basic CF defect improve key clinical outcomes in PWCF, including quality of life (QoL). Clipboard, Search History, and several other advanced features are temporarily unavailable. Thus, differences in the type of microbial infections across patients and even within a single patient over time could explain the low efficacy in some cases and the high patient-to-patient variability in Orkambi response. Thank you for your interest in spreading the word on European Respiratory Society . While patients homozygous for F508del are usually prescribed either lumacaftor plus ivacaftor or tezacaftor plus ivacaftor, patients with only one copy of F508del are rarely prescribed these treatments given their reported inefficacy. Drugs that target the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein are called CFTR modulators. Instead, tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals) appeared to have a more favourable adverse event and drug-drug interaction profile [7, 18, 19] than lumacaftor/ivacaftor. 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]. 4 September 2019. A second phase 3 clinical trial was done for 107 patients homozygous for the F508del mutation, who were randomised for the triple combination versus tezacaftor/ivacaftor for 4 weeks [21]. 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. The first U.S. Food and Drug Administration (FDA) approved drug was ivacaftor (VX-770; Kalydeco, Vertex Pharmaceuticals) [9], a “potentiator” that affected the gating properties of mutant CFTR channel activity (e.g. The introduction of CFTR modulators into clinical practice has resulted in a paradigm shift in therapeutic options, ... PBMCs were isolated from whole blood, using Lymphoprep gradient media (Axis-Shield, Dundee, UK) and cultured in complete RPMI medium (RPMI medium containing 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 U/mL penicillin, 50 μg/mL streptomycin). It is reasonable to speculate that these drugs will alter the natural history of the disease. European Respiratory Society442 Glossop RoadSheffield S10 2PXUnited KingdomTel: +44 114 2672860Email: journals@ersnet.org, Print ISSN: 1810-6838 Online ISSN: 2073-4735, Copyright © 2020 by the European Respiratory Society. Nash EF(1), Middleton PG(2), Taylor-Cousar JL(3).  |  Currently these drugs are confined to people with a limited selection of genetic mutations. First for patients with gating mutations who benefited from Kalydeco, then for those patients with one F508del copy who could benefit from Orkambi, and most recently, patients with at least one F508del copy who can benefit from Trikafta. Among the approved CFTR modulators, Trikafta can be applicable to the largest number of CF patients [20, 22], as it aims to target those with at least one copy of the F508del CFTR mutation, accounting for up to 90% of people with CF [24]. However, there is a main and highly relevant difference between these two studies. NIH Conflict of interest: S. Cuevas-Ocaña has nothing to disclose. The clinical trial of ivacaftor showed a reduction of sweat chloride concentration under the CF diagnostic range and an increase in lung function of 10% [9, 11]. The introduction of CFTR modulator therapy including Tezacaftor and Ivacaftor/ VX-659 presents an ideal opportunity to collect, catalogue and analyse BAL and sputum samples for the analysis of infectious and inflammatory markers prior to and after treatment. Kalydeco (ivacaftor) is a CFTR potentiator developed by Vertex Pharmaceuticals. Conflict of interest: O. Laselva has nothing to disclose. These CFTR modulators are each approved for specific mutations and age groups. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. G551D, S549N, R117H, R347P) [10]. Copyright © 2018 Elsevier Ltd. All rights reserved. CFTR modulators are a class of drugs which directly target the defective CFTR protein in cystic fibrosis (CF), improving its function with resultant clinical improvements. CFTR modulators. Author information: (1)West Midlands Adult Cystic Fibrosis Centre, University Hospitals Birmingham NHS Foundation Trust, Bordesley Green East, Birmingham, United Kingdom. Life-saving drugs, also known as precision medicines, CFTR modulators and modulator therapies, work to tackle the underlying cause of cystic fibrosis. It has been demonstrated that lumacaftor acts to stabilise the mutant CFTR in the early stages of biogenesis by interacting directly with the CFTR protein [14, 15]. The aims of my research were to investigate the mechanisms Of action of small-molecule CFTR modulators that regulate CFTR function. Recent evidence suggests respiratory viral infection may trigger the muco-inflammatory phenotype observed in the CF airways. 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]. We do not capture any email address. The triple CFTR modulation therapy demonstrated good tolerability with only mild or moderate adverse effects and very low rate of discontinuation [20, 21]. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. If CFTR modulators are to form the basis for personalised medicine in CF, effective modulators will be needed to treat the full range of CFTR genotypes found in the CF population.12 In addition, more potent alternatives to currently approved systemic CFTR modulators will be needed to increase the magnitude of benefit that can be achieved with respect to clinical outcomes. Epub 2012 Jun 26. Electronic address: edward.nash@heartofengland.nhs.uk. 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. 2018 Jun 1;197(11):1433-1442. doi: 10.1164/rccm.201710-1983OC. 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. However, it should not be forgotten that there still remains 10% of the CF population who do not have a targeted CFTR modulator treatment. Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. CFTR modulators are a class of drugs which directly target the defective CFTR protein in cystic fibrosis (CF), improving its function with resultant clinical improvements. THERANOSTICS BY TESTING CFTR MODULATORS … In addition, scientists are comparing and trying to elucidate the robustness of current methods and markers used to evaluate the benefit of these new modulation therapies [27, 46, 47]. The US figures came from data that predated the era of CFTR modulator therapy, whilst the UK data included use of ivacaftor in just 5% of the patients for the latter 3 years, so cannot have had an appreciable effect on long term mortality figures. 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