ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies.
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ABSTRACT:
SUBMITTER: Mall MA
PROVIDER: S-EPMC7758539 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies.
The European respiratory journal 20201224 6
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Project description:Highly effective modulator therapies dramatically improve the prognosis for those with cystic fibrosis (CF). The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) benefits many, but not all, of those with the most common F508del mutation in the CF transmembrane conductance regulator (CFTR). Here, we showed that poor sweat chloride concentration responses and lung function improvements upon initiation of ETI were associated with elevated levels of active TGF-β1 in the upper airway. Furthermore, TGF-β1 impaired the function of ETI-corrected F508del-CFTR, thereby increasing airway surface liquid (ASL) absorption rates and inducing mucus hyperconcentration in primary CF bronchial epithelial cells in vitro. TGF-β1 not only decreased CFTR mRNA, but was also associated with increases in the mRNA expression of TNFA and COX2 and TNF-α protein. Losartan improved TGF-β1-mediated inhibition of ETI-corrected F508del-CFTR function and reduced TNFA and COX2 mRNA and TNF-α protein expression. This likely occurred by improving correction of mutant CFTR rather than increasing its mRNA (without an effect on potentiation), thereby reversing the negative effects of TGF-β1 and improving ASL hydration in the CF airway epithelium in vitro. Importantly, these effects were independent of type 1 angiotensin II receptor inhibition.
| S-EPMC9151698 | biostudies-literature
Project description:Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3' and 5' regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.
| S-EPMC8621375 | biostudies-literature
Project description:BackgroundWe recognize an unprecedented opportunity to study the effects of withdrawing one or more chronic treatments in people with CF (PwCF) who benefit greatly from CFTR modulator therapy, but feasibility and acceptance of such a study within the community is unknown.MethodsWe surveyed PwCF, their families, and their acquaintances between November 16, 2018, and December 2, 2018, and CF clinicians between December 19, 2018, and January 2, 2019, about treatment withdrawal research. We sought feedback from these groups about their level of interest in this research, the consistency with which they were taking modulator and non-modulator treatments, the ways in which they conceptualized health changes, and what chronic non-modulator treatments they were most interested in stopping. We also asked for stakeholder perspectives on the design of a treatment withdrawal trial, but we intend to report these perspectives elsewhere.ResultsEighty percent (541/675) of CF community respondents and 95% (206/218) of CF clinicians said that a trial of treatment simplification should be performed in the context of highly effective modulator therapy. Most current CFTR modulator users (292/359, 81%) have not stopped another chronic treatment. Worsening lung function by spirometry or increased daily symptoms were important health indicators. PwCF, their families, and/or their acquaintances ranked airway clearance techniques and inhaled antibiotics as the most burdensome treatments.ConclusionsThere is considerable support among the CF community and CF clinicians in the U.S. for controlled trials to assess the safety and impact of treatment simplification in patients taking highly effective modulator therapy.
| S-EPMC7239731 | biostudies-literature
Project description:Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1?, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1? was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1? only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1? and pro-IL-1? mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.
| S-EPMC7062465 | biostudies-literature
Project description:Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.
| S-EPMC4582929 | biostudies-literature
Project description:Cystic fibrosis (CF) is a recessive inherited disease caused by mutations affecting anion transport by the epithelial ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The disease is characterized by mucus accumulation in the airways and intestine, but the major cause of mortality in CF is airway mucus accumulation, leading to bacterial colonization, inflammation and respiratory failure. Several drug targets are under evaluation to alleviate airway mucus obstruction in CF and one of these targets is the epithelial sodium channel ENaC. To explore effects of ENaC inhibitors on mucus properties, we used two model systems to investigate mucus characteristics, mucus attachment in mouse ileum and mucus bundle transport in piglet airways. We quantified mucus attachment in explants from CFTR null (CF) mice and tracheobronchial explants from newborn CFTR null (CF) piglets to evaluate effects of ENaC or sodium/hydrogen exchanger (NHE) inhibitors on mucus attachment. ENaC inhibitors detached mucus in the CF mouse ileum, although the ileum lacks ENaC expression. This effect was mimicked by two NHE inhibitors. Airway mucus bundles were immobile in untreated newborn CF piglets but were detached by the therapeutic drug candidate AZD5634 (patent WO, 2015140527). These results suggest that the ENaC inhibitor AZD5634 causes detachment of CF mucus in the ileum and airway via NHE inhibition and that drug design should focus on NHE instead of ENaC inhibition.
| S-EPMC8477379 | biostudies-literature
Project description:BackgroundLittle is known about how new therapies that partially correct the basic cystic fibrosis (CF) defect (ivacaftor and lumacaftor) might alter hormonal contraceptive effectiveness, impact pregnancy outcomes, or affect pregnancy timing. Examination of pregnancy rates among CF women during periods of CFTR modulator therapy initiation will provide foundation for further research in this area.MethodsThe Cystic Fibrosis Foundation Patient Registry was used to examine pregnancy rates and outcomes by genotype class before, during, and after the introduction of CFTR modulator therapies between 2005 and 2014.ResultsAmong women with CF, ages 15-44years, there was a slight downward trend in annual pregnancy rates from 2005 to 2014 (2% reduction per year, p=0.041). Among women with G551D, pregnancy rates during phase 3 ivacaftor trial years was 14.4/1000 women-years compared to 34.0/1000 prior to the trial period (relative risk [RR]=0.65; 95% CI=0.43-0.96; p=0.011) and 38.4/1000 after drug approval in June 2012 (RR=1.52 post-approval compared to trial period; 95% CI=1.26, 1.83; p<0.001). Pregnancy outcomes did not significantly change between 2005 and 2014 for any genotype class.ConclusionEvidence of significantly increased numbers of pregnancies among women taking approved CFTR modulators is important because of the unknown risk to pregnancy and fetal outcomes. Increases may be temporary following pregnancy prevention during controlled clinical trials, or from altered perceptions about maternal survival with new approved treatments. As more women with CF become eligible to receive modulators, the CF community must study their effect on contraceptive efficacy and safety during pregnancy. With increased health and survival due to modulation, family planning topics will become more common in CF.
| S-EPMC5550358 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) is a chronic multi-systemic disease that requires a complex daily treatment regimen. Therefore, there is sub-optimal adherence to CF therapies, and it was shown to impact its clinical and economic burden. Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are high-cost medications that demonstrated significant benefit in clinical trials. The aim of this study was to evaluate the safety, usability, and efficacy of the ReX platform in medication management of CFTRm for the treatment of people with CF (pwCF).MethodsReX is a patient engagement platform consisting of a cloud-based management system and a cell-enabled handheld device intended to dispense oral medication into the patient's mouth, following a pre-programmed treatment protocol. It provides real-time adherence data to caregivers and timely, personalized reminders to patients. This is a prospective multi-center open study for pwCFs older than 12 years, who had been prescribed CFTRm [elexacaftor/tezacaftor/ivacaftor (ETI) or tezacaftor/ivacaftor (TI)], and provided consent to use ReX platform to receive CFTRm and record their health condition. Study duration was 12-24 months, with clinic visits where physical examination, body mass index (BMI), and pulmonary function tests were performed, and user experience questionnaires were filled in.ResultsTen pwCFs from two CF centers in Israel were included. The mean age was 31.5 years (range 15-74 years); eight were taking ETI and two TI. Median adherence to CFTRm was 97.5% (range 70%-100%) in the first year and 94% (range 84%-99%) in the second year, which is higher than the previously reported CFTRm adherence of ∼80%. No adverse events related to the use of the platform were reported. Patients reported ReX to be valuable to their treatment management and user friendly. Estimated mean forced expiratory volume in 1 s (FEV1%) increased from 74.4% to 80.8% (p = 0.004) over 2 years. Similarly, estimated BMI percentile increased from 53.5 to 59.0 (p < 0.001).ConclusionsUsing the ReX platform in medication management of pwCF treated by CFTRm is safe, easy to use, and effective in improving the adherence to treatment and the clinical outcomes. Consequently, this device may potentially reduce costs to healthcare providers. Further larger and long-term studies are required to examine the clinical benefits of the ReX platform.
| S-EPMC10766369 | biostudies-literature
Project description:BackgroundElexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis.MethodsThis prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7).ResultsNineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5 ml/min/1.73 m² at M0 vs. 103.3 ml/min/1.73 m² at M7; P = .17). There was a significant reduction in aldosterone level (370.3 pmol/l at M0 vs. 232.4 pmol/l at M7; P = .02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P = .03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6 mmol/d at M0 vs. 3.8 mmol/d at M7; P = .01).ConclusionThese findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.
| S-EPMC11443170 | biostudies-literature
Project description: Not available
| S-EPMC6513216 | biostudies-literature