CFTR Modulators for the Treatment of Cystic Fibrosis.
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ABSTRACT:
SUBMITTER: Pettit RS
PROVIDER: S-EPMC4103577 | biostudies-other | 2014 Jul
REPOSITORIES: biostudies-other
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Project description:Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride channel responsible for ion flow across epithelial surfaces of lung, sinuses, pancreas, intestine, and liver. Researchers have grouped CFTR genetic mutations into various protein defects: reduced protein synthesis (class 1 mutations), abnormal protein folding and maturation (class 2 mutation), and abnormal gating (class 3 mutation). These mutations usually present as severe forms of CF due to complete absence of CFTR at cell surfaces. Milder forms (eg, protein maturation and conductance defects, classes 4-6) present as less severe forms of CF related to the presence of CFTR at the cell surface. Differences in severity are directly due to CFTR function which is based on the severity of CFTR mutation. This knowledge has proven useful for designing therapy for individual mutations and mutation classes. The discovery and US Food and Drug Administration approval of Kalydeco® (ivacaftor) in early 2011 marked the beginning of a new era of therapies that are focused on improving defective CFTR protein function. However, due to its specificity for the G551D mutation, ivacaftor only benefitŝ5% of CF patients. Approximately 50% of CF patients have two copies of the F508Del mutation, while other CF patients carry only one copy of this gene. More recently, Orkambi®, a two compound medication composed of lumacaftor and ivacaftor, has provided the foundation necessary to further build on molecular concepts of: correction of trafficking, potentiation, and amplification of defective CFTR. These new concepts will form the basis of future CF therapies and extend CFTR treatment to almost 50% of CF patients. Evolving knowledge of the molecular mechanisms responsible for defective CFTR has prompted new research focused on "repair" of each phase of CFTR expression and function, thus creating a new class of combination "CFTR correctors" referred to as "triplet CFTR compounds." This article will review how patients can be selected and treated with these newer agents that are based on specific mutations. In the future, many CF practitioners have expectations that initiation of treatment for CF patients will occur simply by use of biomarkers of CFTR expression (eg, sweat chloride, nasal potential difference, rectal organoids) rather than testing for specific mutations. As continued research identifies biomarkers with greater specificity and which predict clinical response, therapies can potentially be tailored to individual responses.
| S-EPMC6287538 | biostudies-literature
Project description:Despite the addition of cystic fibrosis transmembrane conductance regulator (CFTR) modulators to the cystic fibrosis (CF) treatment regimen, patients with CF continue to suffer from chronic bacterial infections that lead to progressive respiratory morbidity. Host immunity, and macrophage dysfunction specifically, has an integral role in the inability of patients with CF to clear bacterial infections. We sought to characterize macrophage responses to CFTR modulator treatment as we hypothesized that there would be differential effects based on patient genotype. Human CF and non-CF peripheral blood monocyte-derived macrophages (MDMs) were analyzed for CFTR expression, apoptosis, polarization, phagocytosis, bacterial killing, and cytokine production via microscopy, flow cytometry, and ELISA-based assays. Compared to non-CF MDMs, CF MDMs display decreased CFTR expression, increased apoptosis, and decreased phagocytosis. CFTR expression increased and apoptosis decreased in response to ivacaftor or lumacaftor/ivacaftor therapy, and phagocytosis improved with ivacaftor alone. Ivacaftor restored CF macrophage polarization responses to non-CF levels and reduced Pseudomonas aeruginosa bacterial burden, but did not reduce other bacterial loads. Macrophage inflammatory cytokine production decreased in response to ivacaftor alone. In summary, ivacaftor and lumacaftor/ivacaftor have differential impacts on macrophage function with minimal changes observed in CF patients treated with lumacaftor/ivacaftor. Overall improvements in macrophage function in ivacaftor-treated CF patients result in modestly improved macrophage-mediated bacterial killing.
| S-EPMC6244248 | biostudies-literature
Project description:Cystic fibrosis (CF) is the most common life-threatening monogenic disease afflicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients' debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients.
| S-EPMC5011145 | biostudies-literature
Project description:Cystic fibrosis (CF) is characterised by the accumulation of viscous adherent mucus in the lungs. While several hypotheses invoke a direct relationship with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (i.e. acidic airway surface liquid (ASL) pH, low bicarbonate (HCO3-) concentration, airway dehydration), the dominant biochemical alteration of CF mucus remains unknown. We characterised a novel cell line (CFTR-KO Calu3 cells) and the responses of human bronchial epithelial (HBE) cells from subjects with G551D or F508del mutations to ivacaftor and elexacaftor-tezacaftor-ivacaftor. A spectrum of assays such as short-circuit currents, quantitative PCR, ASL pH, Western blotting, light scattering/refractometry (size-exclusion chromatography with inline multi-angle light scattering), scanning electron microscopy, percentage solids and particle tracking were performed to determine the impact of CFTR function on mucus properties. Loss of CFTR function in Calu3 cells resulted in ASL pH acidification and mucus hyperconcentration (dehydration). Modulation of CFTR in CF HBE cells did not affect ASL pH or mucin mRNA expression, but decreased mucus concentration, relaxed mucus network ultrastructure and improved mucus transport. In contrast with modulator-treated cells, a large fraction of airway mucins remained attached to naïve CF cells following short apical washes, as revealed by the use of reducing agents to remove residual mucus from the cell surfaces. Extended hydration, but not buffers alkalised with sodium hydroxide or HCO3-, normalised mucus recovery to modulator-treated cell levels. These results indicate that airway dehydration, not acidic pH and/or low [HCO3-], is responsible for abnormal mucus properties in CF airways and CFTR modulation predominantly restores normal mucin entanglement.
| S-EPMC8859811 | 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:Background: Newly developed quantitative chest computed tomography (CT) outcomes designed specifically to assess structural abnormalities related to cystic fibrosis (CF) lung disease are now available. CFTR modulators potentially can reduce some structural lung abnormalities. We aimed to investigate the effect of CFTR modulators on structural lung disease progression using different quantitative CT analysis methods specific for people with CF (PwCF). Methods: PwCF with a gating mutation (Ivacaftor) or two Phe508del alleles (lumacaftor-ivacaftor) provided clinical data and underwent chest CT scans. Chest CTs were performed before and after initiation of CFTR modulator treatment. Structural lung abnormalities on CT were assessed using the Perth Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), airway-artery dimensions (AA), and CF-CT methods. Lung disease progression (0-3 years) in exposed and matched unexposed subjects was compared using analysis of covariance. To investigate the effect of treatment in early lung disease, subgroup analyses were performed on data of children and adolescents aged <18 years. Results: We included 16 modulator exposed PwCF and 25 unexposed PwCF. Median (range) age at the baseline visit was 12.55 (4.25-36.49) years and 8.34 (3.47-38.29) years, respectively. The change in PRAGMA-CF %Airway disease (-2.88 (-4.46, -1.30), p = 0.001) and %Bronchiectasis extent (-2.07 (-3.13, -1.02), p < 0.001) improved in exposed PwCF compared to unexposed. Subgroup analysis of paediatric data showed that only PRAGMA-CF %Bronchiectasis (-0.88 (-1.70, -0.07), p = 0.035) improved in exposed PwCF compared to unexposed. Conclusion: In this preliminary real-life retrospective study CFTR modulators improve several quantitative CT outcomes. A follow-up study with a large cohort and standardization of CT scanning is needed to confirm our findings.
| S-EPMC10127680 | biostudies-literature
Project description:Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that approved F508del CFTR correctors VX809/VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del-CFTR. Mechanistically, F508del-CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CBP. Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.
| S-EPMC6668689 | biostudies-literature
Project description:The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease.
| S-EPMC10019140 | biostudies-literature
Project description:Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o-) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.
| S-EPMC6124440 | biostudies-literature
Project description:BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulators are disease-modifying medications for cystic fibrosis (CF) and are shown to be efficacious for only specific CFTR mutations. CFTR mutation frequency varies by ancestry, which is different from but related to demographic racial and ethnic group. Eligibility for CFTR modulator therapy has not been previously reported by race and ethnicity.MethodsWe conducted a cross-sectional study of patients in the 2018 CF Foundation Patient Registry. We analyzed the percentage of patients in each US Census defined racial and ethnic group eligible for CFTR modulators based on CFTR mutations approved by the US FDA and then based on both mutations and FDA approval by age. We compared lung function based on CFTR modulator eligibility and prescription.FindingsBased on CFTR mutations alone, 92.4% of non-Hispanic White patients, 69.7% of Black/African American patients, 75.6% of Hispanic patients, and 80.5% of other race patients eligible for CFTR modulators. For each CFTR modulator, Black/African American patients were least likely to have eligible mutations, and non-Hispanic White patients were most likely. There was no difference in the disparity between racial and/or ethnic groups with the addition of current FDA approval by age. The lowest pulmonary function in the cohort was seen in non-Hispanic White, Black/African American, and Hispanic patients not eligible for CFTR modulators.InterpretationPatients with CF from minority groups are less likely to be eligible for CFTR modulators. Because people with CF who are racial and ethnic minorities have increased disease severity and earlier mortality, this will further contribute to health disparities.
| S-EPMC8137541 | biostudies-literature