cftr modulators
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Author(s):  
Ciaran A Shaughnessy ◽  
Sangya Yadav ◽  
Preston E Bratcher ◽  
Pamela L Zeitlin

Cystic fibrosis (CF) is a genetic disease caused by mutations of the gene encoding a cAMP-activated Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR modulator therapies consist of small-molecule drugs that rescue mutant CFTR. Regimens of single or combinations of CFTR modulators still rely on endogenous levels of cAMP to regulate CFTR activity. We investigated CFTR activation by the natural mediator prostaglandin E2 (PGE2) and lubiprostone and tested the hypothesis that receptor-mediated CFTR activators can be used in combination with currently available CFTR modulators to increase function of mutant CFTR. Primary cultured airway epithelia were assayed in Ussing chambers. Experimental CFTR activators and established CFTR modulators were applied for 24 h and/or acutely and analyzed for their effect on CFTR activity as measured by changes in short-circuit current (ISC). In non-CF airway epithelia, acute application of lubiprostone and PGE2 activated CFTR to levels comparable to forskolin. Pre-treatment (24 h) with antagonists to prostaglandin receptors EP2 and EP4 abolished the ability of lubiprostone to acutely activate CFTR. In F508del homozygous airway epithelia pre-treated with the triple combination of elexacaftor, tezacaftor, and ivacaftor (ELEXA/TEZ/IVA; i.e., Trikafta), acute application of lubiprostone was able to maximally activate CFTR. Prolonged (24 h) co-treatment of F508del homozygous epithelia with ELEXA/TEZ/IVA and lubiprostone increased acute CFTR activation by ~60% compared to treatment with ELEXA/TEZ/IVA alone. This work establishes the feasibility of targeting prostaglandin receptors to activate CFTR on the airway epithelia and demonstrates that co-treatment with lubiprostone can further restore modulator-rescued CFTR.


2022 ◽  
Vol 11 (2) ◽  
pp. 318
Author(s):  
Renée V. E. Dagenais ◽  
Victoria C. Su ◽  
Bradley S. Quon

In the original article [...]


2021 ◽  
Vol 11 (12) ◽  
pp. 1376
Author(s):  
Danya Muilwijk ◽  
Marlou Bierlaagh ◽  
Peter van Mourik ◽  
Jasmijn Kraaijkamp ◽  
Renske van der Meer ◽  
...  

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.


mBio ◽  
2021 ◽  
Author(s):  
Samantha L. Durfey ◽  
Sudhakar Pipavath ◽  
Anna Li ◽  
Anh T. Vo ◽  
Anina Ratjen ◽  
...  

Recent work shows that people with cystic fibrosis (CF) and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy.


2021 ◽  
Vol 14 (12) ◽  
pp. 1296
Author(s):  
Roberto Sabbadini ◽  
Emanuela Pesce ◽  
Alice Parodi ◽  
Eleonora Mustorgi ◽  
Santina Bruzzone ◽  
...  

Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π–π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I–IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the “in-silico” prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3380
Author(s):  
Monica Averna ◽  
Paola Melotti ◽  
Claudio Sorio

Cystic fibrosis in characterized by pulmonary bacterial colonization and hyperinflammation. Lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells of patients with CF express functional CFTR and are directly affected by altered CFTR expression/function, impairing their ability to resolve infections and inflammation. However, the mechanism behind and the contribution of leukocytes in the pathogenesis of CF are still poorly characterized. The recent clinical introduction of specific CFTR modulators added an important tool not only for the clinical management of the disease but also to the investigation of the pathophysiological mechanisms related to CFTR dysfunction and dysregulated immunity. These drugs treat the basic defect in cystic fibrosis (CF) by increasing CFTR function with improvement of lung function and quality of life, and may improve clinical outcomes also by correcting the dysregulated immune function that characterizes CF. Measure of CFTR function, protein expression profiling and several omics methods were used to identify molecular changes in freshly isolated leukocytes of CF patients, highlighting two roles of leukocytes in CF: one more generally related to the mechanism(s) causing immune dysregulation in CF and unresolved inflammation, and another more applicative role, which identifies in myeloid cells, an important tool predictive of the therapeutic response of CF patients. In this review we will summarize available data on CFTR expression and function in leukocyte populations and will discuss potential clinical applications based on available data.


Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210112
Author(s):  
Daniel H. Tewkesbury ◽  
Rebecca C. Robey ◽  
Peter J. Barry

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.


2021 ◽  
Vol 8 (1) ◽  
pp. e000998
Author(s):  
Kathryn Bresnick ◽  
Emilio Arteaga-Solis ◽  
Stefanie J Millar ◽  
Glen Laird ◽  
Cecile LeCamus

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF <12 years of age prior to the first approval of CFTR modulators.MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to <2 years, 2 to <6 years and 6 to <12 years) and genotype (F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to <12-year-olds, mean (SD) per cent predicted FEV1 in 1 s was 92.6% (17.5%). Among all children <12 years of age, the mean (SD) all-cause hospitalisation and pulmonary exacerbation rates in 2011 were 0.4 (1.0) and 0.3 (0.8), respectively. Most (93.6%) had ≥1 positive lung microbiology culture. CF-related medication and nutritional supplementation use was common across all ages and genotypes. More than half (54.7%) had ≥1 CF-related complication. Evidence of disease burden was observed across the age and genotype groups studied.ConclusionsPrior to the approval of the first CFTR modulator therapies in children <12 years of age, CF was associated with substantial BOI from an early age—including respiratory infections, hospitalisations/pulmonary exacerbations, need for supplemental nutrition and pharmacological treatments—irrespective of genotype.


Author(s):  
Stephanie Kuek ◽  
John Massie

Introduction: Diagnosis and management of CRMS/CFSPID and cystic fibrosis (CF) with mild phenotypes remains challenging, and this extends to expanding practice with the use of CFTR modulators. Case: We describe a case of an 18-year-old man with p.F508del/p.Arg117His(7T) initially presenting with CRMS/CFSPID. He went on to be diagnosed with pancreatic sufficient CF with minimal lung disease and no bronchiectasis. However, he has had significant CFTR-related symptoms with recurrent pancreatitis and chronic sinusitis. These non-pulmonary symptoms resolved following introduction of the CFTR modulator ivacaftor. Discussion/ Conclusion: Diagnosis and follow up of CRMS/CFSPID infants remains challenging, with most guidelines based on consensus opinion. Care for those with mild CF phenotypes, CRMS/CFSPID and those with CFTR-RD must be individualised, and open dialogue, education and patient centred care is necessary to ascertaining which patients might benefit from management in a multidisciplinary CF clinic and treatment. There may be a role for expanding the use of CFTR modulators to include non-pulmonary manifestations of CFTR dysfunction in some cases.


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