doi: 10.1136/thoraxjnl-2011-200393, Clarke, L. A., Awatade, N. T., Felício, V. M., Silva, I. Fibros. Med. They result from alternative splicing, promoter or missense mutations. These findings indicate that other existing and approved drugs for unrelated disease indications might have the potential to correct or circumvent CFTR dysfunction and should be exploited in the pre-clinical setting. A subsequent series of experimental and clinical studies led to the extended approval of ivacaftor to treat CF patients carrying other gating mutations (Yu et al., 2012; De Boeck et al., 2014). (2019). Co-administration of lumacaftor/ivacaftor in vitro also reduced pro-inflammatory responses induced by P. aeruginosa exoproducts in well-differentiated human bronchial epithelial cells (F508del/F508del genotype) (Ruffin et al., 2018). The effects of certain therapies may also be exploited at an individual level in ex vivo patient-derived specimens, such as primary bronchial/nasal epithelial cells, and intestinal/respiratory organoids (Fulcher and Randell, 2013; Dekkers et al., 2016a; Dekkers et al., 2016b; Pranke et al., 2017; Awatade et al., 2018; Brewington et al., 2018; Chen et al., 2018; Berkers et al., 2019; Merket et al., 2019). Pediatr. doi: 10.1038/354526a0, Davies, J. C., Cunningham, S., Harris, W. T., Lapey, A., Regelmann, W. E., et al. 9 (9), 1224–1243. 4 (6), 8–9. Fibros. EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1. In fact, a significant but variable clinical responsiveness was observed in clinical trials with CFTR modulators in patients carrying at least one G551D mutation (Ramsey et al., 2011; Rowe et al., 2014) or in F508del-homozygous patients (Boyle et al., 2014; Wainwright et al., 2015; Donaldson et al., 2018a), which suggests that patient responsiveness to a certain therapy is influenced not only by the CF genotype but also by the genetic background and/or epigenetic factors. Such findings served as basis for the extended approval of tezacaftor/ivacaftor for patients aged ≥6 years. Chronic ivacaftor exposure (>1 µM) reduces lumacaftor-rescued CFTR in F508del-expressing cells (Cholon et al., 2014; Veit et al., 2014), although lower concentrations of ivacaftor (≤1 µM) may prevent such negative effect (Matthes et al., 2016). Impact of pulmonary exacerbations and lung function on generic health-related quality of life in patients with cystic fibrosis. Biol. Furthermore, the fourth extracellular loop possesses two N-linked glycosylation sites (N894 and N900), which are assessed by the ER quality control during the protein folding process. Health Med. Figure 1 From gene to protein structure. doi: 10.1513/AnnalsATS.201609-689OC, Rubenstein, R. C., Egan, M. E., Zeitlin, P. L. (1997). Physiol. Strategies to adapt and optimize trial design and deliver for speed and efficacy have been discussed, including the use of patient-derived specimens, power calculations to compensate for group sampling, and N-of-1 and “basket” trials (Matthes et al., 2018; Amaral et al., 2019; Davies et al., 2019b). Chappe, V., Hinkson, D. A., Zhu, T., Chang, X. European Cystic Fibrosis Society. Fibros. 50 (12), 1224–1229. Angew. Despite therapeutic effects observed in phase II clinical trials (Sermet-Gaudelus et al., 2010; Wilschanski et al., 2011), ataluren treatment only demonstrated a favorable trend, albeit not significant, to improve ppFEV1 of CF patients carrying a nonsense CFTR mutation in at least one allele in a phase III clinical trial (Kerem et al., 2014). Med. (2018). J. Pharmacol. Drug repurposing: progress, challenges and recommendation. Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. Front. Cystic Fibrosis New Zealand. 287 (44), 36639–36649. doi: 10.1016/j.molmed.2011.10.003, Marson, F. A. L., Bertuzzo, C. S., Ribeiro, J. D. (2016). 18 (5), 708–713. Data from US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. 4 (1), 00080–02017. Genet. Chloride impermeability in cystic fibrosis. (2017). doi: 10.1016/j.jcf.2018.12.004, Frost, F. J., Nazareth, D. S., Charman, S. C., Winstanley, C., Walshaw, M. J. Med. These strategies might also be used alone or in combination with CFTR modulators to enhance clinical outcomes. Biol. Nevertheless, it still produces a certain amount of the truncated forms of both partially and fully glycosylated CFTR protein that may respond to CFTR modulators (Haggie et al., 2017; Aksit et al., 2019). (2014). Invest. Fibros. Might brushed nasal cells be a surrogate for CFTR modulator clinical response? Over 2,000 CFTR gene variants have been reported in the Cystic Fibrosis Mutation Database (CFTR1 Database). (A) Distribution according to the percentage of patients carrying the F508del mutation in at least one allele. doi: 10.1016/j.molmed.2018.06.009, Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W., White, G. A., et al. It was demonstrated to selectively increase the expression of immature CFTR protein carrying different mutations without eliciting alteration in the expression of cellular stress response genes (Giuliano et al., 2018). 18 (18), 1–106. doi: 10.1056/NEJMra043184, Rowe, S. M., Sloane, P., Tang, L. P., Backer, K., Mazur, M., Buckley-Lanier, J., et al. Natl. Ann. (2016). A major limitation of these novel pharmaceutical treatments for CF patients, such as the CFTR modulators, is the excessive costs when they reach the market (over US$250,000 per patient per year), which renders difficulties in their availability for many patients worldwide (O'Sullivan et al., 2013; Ferkol and Quinton, 2015; Orestein et al., 2015), especially for those living in low- and middle-income countries (Cohen-Cymberknoh et al., 2016). (2018). Thorax 73 (8), 731–740. Rep. 9 (1), 7234. doi: 10.1038/s41598-019-43652-2, Haggie, P. M., Phuan, P. W., Tan, J. Certain therapeutic benefits may also be more modest in a real-world setting compared to clinical trials, as patients should take these oral medications following specific recommendations, including dietary to ensure better drug absorption and availability in the body. (2018). 151 (7), 912–928. J. Cyst. Journal of Clinical Medicine. The classification has historically been evolving according to the gained knowledge (Collins, 1992; Welsh and Smith, 1993; Wilschanski et al., 1995; Haardt et al., 1999; Rowe et al., 2005), and the current scheme is composed of six classes (Figure 4), although a seventh class has been proposed to separately consider large deletions that may abrogate production of CFTR mRNA (De Boeck and Amaral, 2016; Marson et al., 2016). doi: 10.1038/nchembio.1253, Okiyoneda, T., Veit, G., Sakai, R., Aki, M., Pujihara, T., Higashi, M., et al. Discovery of ABBV-GLPG-3221, a potent corrector of CFTR for the treatment of cystic fibrosis. Lancet Respir. In an era of drugs targeting the underlying defects in CF-causing mutations, the development of symptomatic therapies might appear less attractive. A recent review nicely summarizes the current understanding of CFTR modulators on extra-pulmonary complications in CF (Sergeev et al., 2019). A report pairing in vitro measurement of CFTR function in cell lines and clinical features demonstrated a strong correlation between CFTR function and sweat chloride concentration, and to a lesser extent but still significant with lung function and pancreatic status (McCague et al., 2019). Some reports have also demonstrated that younger patients are more adherent to therapies than adolescents and adults, possibly due to higher parental supervision (Quittner et al., 2014; Shakkottai et al., 2014). A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 2, extension study. Speeding up access to new drugs for CF: considerations for clinical trial design and delivery. PloS Genet. 50 (4), 805–816. Ribbon diagram of the phosphorylated, ATP-bound CFTR in complex with (A) ABBV-974 and (B) ivacaftor. (2015). doi: 10.7326/M16-0858, Strauss, D. G., Blinova, K. (2017). J. Mol. Rep. 7 (1), 7375. doi: 10.1038/s41598-017-07504-1, Pranke, I., Bidou, L., Martin, N., Blanchet, S., Hatton, A., Karri, S., et al. 17 (2), 153–178. (2018). Correction of CFTR function in nasal epithelial cells from cystic fibrosis predicts improvement of respiratory function by CFTR modulators. Australian Cystic Fibrosis Data Registry – Annual Report 2016, Available at: https://www.cysticfibrosis.org.au/getmedia/a3b28200-caeb-4c5a-ad15-98c71a8c7dc8/ACFDR-2016-Annual-Report-Final-Copy-Single-Page-Version.pdf.aspx. Am. Science 329, 805–810. Mol. 2 (7), 539–547. High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel. A new phase III trial was undertaken to exclude patients taking inhaled tobramycin, since it could interfere with ataluren actions on the ribosome; however, no improvements were observed in ppFEV1 and pulmonary exacerbations (NCT02139306). Proc. Am. Furthermore, recent studies have demonstrated that abrupt interruption of CFTR modulator therapy may cause severe clinical consequences. PTI-801 was also less sensitive to the ivacaftor-mediated decrease on CFTR function. Am. Acquired CFTR Dysfunction in … A consistent correlation was found among forskolin-induced swelling of intestinal organoids, sweat chloride concentration and intestinal current measurements of infants with CF (de Winter-de Groot et al., 2018). Mol. (2010). (2014). 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Lancet Respir. Pharmacol. Modulator treatments for cystic fibrosis: effectiveness and value – Evidence report May 3, 2018. Many other variants are still uncharacterized, and in silico tools may be useful to predict the cellular and molecular consequences caused by these alterations (Michels et al., 2019; Pereira et al., 2019), while they are not confirmed in cell models. In this line, amlexanox (Gonzalez-Hilarion et al., 2012) and escin (Mutyam et al., 2016) are drugs already approved for unrelated diseases that demonstrated dual activity by concomitantly increasing the abundance of target transcripts and read-through efficacy for certain CFTR PTC mutations. Studies using genome- and proteome-wide association analyses have identified proteostasis components that could be targeted to rescue CFTR in F508del-expressing cells (Wang et al., 2006; Simpson et al., 2012; Tomati et al., 2018a). Int. 14 (5), e1002462. (2019). Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies. https://www.cftr2.org/. (2016). The effects of this triple combination on F508del-CFTR reached ~50-100% of WT-level correction in cell lines, patient-derived specimens, and in mouse nasal epithelia. (2018). Even though the quality-adjusted life-year (QALY) analysis might not adequately address all concerns for rare diseases, such as CF (Schlander et al., 2014; Pearson et al., 2018), these therapies pose a substantial burden on national healthcare systems, as they are expensive and lifelong. While the identification of single putative binding site for small molecules, such as lumacaftor and ivacaftor, is important to unravel the mechanism(s) of action, multiple binding sites on the CFTR protein remain a possibility. 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. J. Paediatr. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. Lancet 394 (10212), 1940–1948. Inevitably, randomised controlled trials during the development of these … Front. Recently, ASOs developed by SpliSense have also demonstrated to correct aberrant splicing and restore CFTR function in a 3849+10kbC>T-expressing cell line and in primary bronchial epithelial cells (3849+10kbC>T/F508del genotype). Value Health 21 (5), 515–524. Zeitlin, P. L., Diener-West, M., Rubenstein, R. C., Boyle, M. P., Lee, C. K., Brass-Ernst, L. (2002). Chem. 7 (7), e1000155. Figures 2 and 3 are data compiled from the last Patient Registry Report in Australia (Cystic Fibrosis Australia), Brazil (Brazilian Cystic Fibrosis Study Group), Canada (Cystic Fibrosis Canada), Europe (European Cystic Fibrosis Society), New Zealand (Cystic Fibrosis New Zealand), UK (Cystic Fibrosis Trust), and USA (Cystic Fibrosis Foundation). 4 (2), 91–92. (2013). The South African Cystic Fibrosis Registry Initiative (SACFRI): Implementation challenges and initial data. 22 (3), 315–324. Barical, A., Lee, R. E., Randell, S. H., Hawkins, F. (2019). UK Cystic Fibrosis Registry – Annual Data Report 2018, Available at: https://www.cysticfibrosis.org.uk/~/media/documents/the-work-we-do/uk-cf-registry/2018-registry-annual-data-report.ashx?la=en. Rescue of nonsense mutations by amlexanox in human cells. Chem. (2018). 197 (11), 1433–1442. (2018). doi: 10.1016/0092-8674(90)90148-8, Cholon, D. M., Quinney, N. L., Fulcher, M. L., Esther, C. R., Jr., Das, J., Dokholyan, N. V., et al. 61 (1), 198–207. 23 (8), 1380–1393. Tezacaftor/ivacaftor was selected as the backbone for the triple combination based on the more favorable pharmacological properties, including lower cytochrome P450 3A activation (Rowe et al., 2017a; Taylor-Cousar et al., 2017; Donaldson et al., 2018a). It was demonstrated to promote CFTR maturation and PM stability by inhibiting S-nitrosoglutathione reductase in vitro. Soon after co- and post-translational folding, and core glycosylation in the endoplasmic reticulum (ER), CFTR protein traffics to the Golgi complex, where it is fully glycosylated. Cell Death Differ. doi: 10.1371/journal.pbio.1002462, Veit, G., Xu, H., Dreano, E., Avramescu, R. G., Bagdany, N., Beitel, L. K., et al. Cytochrome P450 3A4 induction: lumacaftor versus ivacaftor potentially resulting in significantly reduced plasma concentration of ivacaftor. (2018). The author also thanks Nicoletta Pedemonte (Ph.D.) for the help in preparing Figure 8. doi: 10.1056/NEJMoa022170, Wilschanski, M., Miller, L. L., Shoseyov, D., Blau, H., Rivlin, J., Aviram, M., et al. N. Engl. Expert Opin. (2017). Bioactive thymosin alpha-1 does not influence F508del-CFTR maturation and activity. doi: 10.1124/mol.118.111799, Leonard, A., Lebecque, P., Dingemanse, J., Leal, T. (2012). Combination of correctors rescue ΔF508del-CFTR by reducing its association with Hsp40 and Hsp27. Figure 5 Cellular and molecular defects and potential CF transmembrane conductance regulator (CFTR) modulator approaches. doi: 10.1091/mbc.e12-09-0678, Aksit, M. A., Bowling, A. D., Evans, T. A., Joynt, A. T., Osorio, D., Patel, S., et al. (2018). doi: 10.1016/0092-8674(90)90398-X, Drumm, M. L., Wilkinson, D. J., Smit, L. S., Worrell, R. T., Strong, T. V., Frizzell, R. A., et al. Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics. Invest. Cystic Fibrosis Foundation. (2007). (B) Global distribution by CF genotype: F508del-homozygous, F508del-heterozygous and carrying non-F508del mutations in both alleles. doi: 10.1016/j.omtm.2018.03.006, Durmowicz, A. G., Lim, R., Rogers, H., Rosebraugh, C. J., Chowdhury, B. SLAS Technol. Sci. Correctors are compounds that rescue folding, processing and trafficking to the PM of a CFTR mutant. Fukuda, R. E., Carbone, J channel ( ENaC ) as a therapeutic target cystic... Biological characterization of F508delCFTR protein processing by the potentiator FDL176 ( NCT02768297 NCT03093714! Cftr biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis ( )! Of ABBV-974 fibrosis organoids treatment at age 2-5 years ( KLIMB ) exploited, they did not demonstrate correction! Of morbidity and mortality of these patients for ABBV-974 and ( B ) mutants N1303K and of. 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