Modulátory transmembránového regulátoru vodivosti cystické fibrózy (cystic fibrosis transmembrane conductance regulátor, CFTR) jsou od roku 2012 dostupné ke kauzální léčbě cystické fibrózy. Jde o látky působící na konkrétní mutace či skupiny mutací genu CFTR. Obecně je lze dělit na korektory a potenciátory CFTR proteinu, kde korektory zvyšují množství CFTR proteinu v buněčné membráně, kdežto potenciátory zlepšují jeho funkci. V klinické praxi je v současnosti využíván potenciátor ivakaftor a korektory lumakaftor a tezakaftor. U dalšího korektoru, elexakaftoru, se v nejbližší době předpokládá schválení ke klinickému použití.
CFTR modulators have been available since 2012 for causal treatment of cystic fibrosis. These are substances that affect specific mutations or groups of mutations of the CFTR gene. In general, they can be divided into CFTR correctors and potentiators, where CFTR correctors increase the amount of CFTR protein in the cell membrane, while CFTR potentiators improve its function. In clinical practice, the CFTR potentiator ivacaftor and the CFTR correctors lumacaftor and tezacaftor are currently used. Another CFTR corrector, elexacaftor, is expected to be approved for clinical use in the near future.
- Keywords
- ivakaftor, lumakaftor, tezakaftor, elexakaftor,
- MeSH
- Aminophenols MeSH
- Cystic Fibrosis * immunology therapy MeSH
- Humans MeSH
- Membrane Transport Modulators MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Kauzální léčba cystické fibrózy se v roce 2012 stala klinickou realitou díky modulátorům proteinu CFTR (cystic fibrosis transmembrane conductance regulator). V letošním roce se paleta těchto léků v ČR rozšířila o kombinaci elexakaftor, tezakaftor a ivakaftor pro nosiče alespoň jedné mutace F508del genu CFTR ve věku alespoň 12 let. V případě rozšíření použití i do mladších věkových kategorií bude kauzální léčba dostupná pro 90 % nemocných cystickou fibrózou v ČR.
Causal treatment of cystic fibrosis became a clinical reality in 2012 thanks to the CFTR protein (cystic fibrosis transmembrane conductance regulator) modulators. This year, the range of these drugs in the Czech Republic has expanded by a combination of elexacaftor, tezacaftor and ivacaftor for carriers of at least one F508del mutation of the CFTR gene at the age of at least 12 years. If the use is extended to younger age categories, causal treatment will be available for 90% of CF patients in the Czech Republic.
- Keywords
- elexakaftor,
- MeSH
- Chloride Channel Agonists * administration & dosage adverse effects therapeutic use MeSH
- Cystic Fibrosis * drug therapy MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator drug effects MeSH
- Pyrazoles administration & dosage adverse effects therapeutic use MeSH
- Pyridines administration & dosage adverse effects therapeutic use MeSH
- Pyrrolidines administration & dosage adverse effects therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Cystická fibróza (CF) je vrozené onemocnění vyvolané patogenními variantami genu CFTR. Projevuje se především chronickým sinopulmonálním onemocněním, postižením trávicího ústrojí s poruchou stavu výživy, vysokou koncentrací chloridů v potu a obstruktivní azoospermií. Kromě tradiční symptomatické léčby je v posledních letech dostupná modulátorová terapie, která cílí na chybějící nebo nefunkční CFTR protein. U nosičů alespoň jedné mutace F508del je indikována léčba kombinací elexakaftor, tezakaftor a ivakaftor, z ostatních mutací jsou pro monoterapii ivakaftorem vhodní nosiči tzv. gating mutací (např. G551D). Modulátorová léčba prokázala v klinických studiích zlepšení plicních funkcí, stavu výživy a kvality života a zásadně zlepšila prognózu nemocných CF. Hlavní nevýhodou modulátorové léčby je její vysoká cena.
Cystic fibrosis (CF) is a hereditary disease caused by pathogenic variants of the CFTR gene. It is mainly manifested by chronic sinopulmonary disease, digestive tract involvement with nutritional status disorders, high sweat chloride concentration and obstructive azoospermia. In addition to traditional symptomatic treatment, modulator therapy has become available in recent years, which targets the missing or dysfunctional CFTR protein. For carriers of at least one F508del mutation, treatment with a combination of elexacaftor, tezacaftor and ivacaftor is indicated; among other mutations, carriers of so-called gating mutations (e.g. G551D) are suitable for ivacaftor monotherapy. Modulator therapy has been shown in clinical trials to improve lung function, nutritional status, and quality of life, and leads to a significantly better prognosis for patients with CF. The main disadvantage of modulator therapy is its high cost.
- Keywords
- gen CFTR, modulátory CFTR proteinu,
- MeSH
- Cystic Fibrosis * therapy MeSH
- Humans MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Cystic Fibrosis * drug therapy epidemiology genetics MeSH
- Humans MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator * drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Letter MeSH
- Geographicals
- Europe, Eastern MeSH
CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.
- MeSH
- Cystic Fibrosis drug therapy genetics MeSH
- Clinical Trials as Topic organization & administration MeSH
- Consensus MeSH
- Humans MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator drug effects MeSH
- Drug Development organization & administration MeSH
- Research Design MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Chloride Channels analysis MeSH
- Cystic Fibrosis * diagnosis drug therapy physiopathology MeSH
- Clinical Chemistry Tests MeSH
- Humans MeSH
- Membrane Transport Modulators therapeutic use MeSH
- Sweat MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator adverse effects drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Comment MeSH
RATIONALE: Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). OBJECTIVES: To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data. METHODS: Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature. RESULTS: Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit. CONCLUSIONS: Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.
- MeSH
- Cystic Fibrosis * drug therapy genetics metabolism MeSH
- Homozygote MeSH
- Ion Transport MeSH
- Humans MeSH
- Mutation MeSH
- Organoids metabolism MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: We previously documented that elevated HE4 plasma concentration decreased in people with CF (pwCF) bearing the p.Gly551Asp-CFTR variant in response to CFTR modulator (CFTRm) ivacaftor (IVA), and this level was inversely correlated with the FEV1% predicted values (ppFEV1). Although the effectiveness of lumacaftor (LUM)/IVA in pwCF homozygous for the p.Phe508del-CFTR variant has been evaluated, plasma biomarkers were not used to monitor treatment efficacy thus far. METHODS: Plasma HE4 concentration was examined in 68 pwCF drawn from the PROSPECT study who were homozygous for the p.Phe508del-CFTR variant before treatment and at 1, 3, 6 and 12 months after administration of LUM/IVA therapy. Plasma HE4 was correlated with ppFEV1 using their absolute and delta values. The discriminatory power of delta HE4 was evaluated for the detection of lung function improvements based on ROC-AUC analysis and multiple regression test. RESULTS: HE4 plasma concentration was significantly reduced below baseline following LUM/IVA administration during the entire study period. The mean change of ppFEV1 was 2.6% (95% CI, 0.6 to 4.5) by 6 months of therapy in this sub-cohort. A significant inverse correlation between delta values of HE4 and ppFEV1 was observed especially in children with CF (r=-0.7053; p<0.0001). Delta HE4 predicted a 2.6% mean change in ppFEV1 (AUC: 0.7898 [95% CI 0.6823-0.8972]; P < 0.0001) at a cut-off value of -10.7 pmol/L. Moreover, delta HE4 independently represented the likelihood of being a responder with ≥ 5% delta ppFEV1 at 6 months (OR: 0.89, 95% CI: 0.82-0.95; P = 0.001). CONCLUSIONS: Plasma HE4 level negatively correlates with lung function improvement assessed by ppFEV1 in pwCF undergoing LUM/IVA CFTRm treatment.
- MeSH
- Chloride Channel Agonists therapeutic use MeSH
- Aminophenols therapeutic use MeSH
- Aminopyridines therapeutic use MeSH
- Benzodioxoles therapeutic use MeSH
- Cystic Fibrosis * diagnosis drug therapy genetics MeSH
- Child MeSH
- Drug Combinations MeSH
- Homozygote MeSH
- Humans MeSH
- Mutation MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial-mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.
- MeSH
- Cystic Fibrosis metabolism pathology MeSH
- Epithelial-Mesenchymal Transition MeSH
- HEK293 Cells MeSH
- Nuclear Proteins metabolism MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Oncogenes genetics MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator metabolism MeSH
- Twist-Related Protein 1 metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cystická fibróza (CF) představuje nejčastější život limitující dědičné onemocnění, které postihuje přibližně 85 000 pacientů po celém světe. Příčinou onemocnění je mutace v genu CFTR (cystic fibrosis conductance regulator), který plní funkci iontového přenašeče na apikální membráně epitelových buněk. Léčba tohoto závažného onemocnění byla donedávna pouze symptomatická. Možnosti kauzální terapie mířící přímo na opravu molekulárního defektu CFTR proteinu se objevily v roce 2012, kdy byl registrován první lék ze třídy tzv. CFTR modulátorů opravujících funkci tohoto proteinu. V současné době máme k dispozici čtyři CFTR modulátory, všechny dohromady mohou účinkovat až u 90 % pacientů s CF. Určujícím parametrem příslušné léčby je genotyp pacienta.
Cystic fibrosis (CF) is the most common life‑shortening genetic disease. It affects approximately 85,000 people worldwide. The disease is caused by bi‑allelic mutations in the gene encoding the CFTR (cystic fibrosis conductance regulator) protein, which plays a major role in ion transport across the apical membrane of the epithelial cells. Until recently, treatment of this disease was solely symptomatic. Causal therapy targeting molecular defect of CFTR protein has been available since 2012, when first therapeutic agent was registered. These therapeutic agents (CFTR modulators) repair synthesis and function of the CFTR protein. Currently, there are four CFTR modulators available and all together they can work in up to 90% of all patients with CF. Determining parameter of the respective treatment is the genotype of the patient.
