(2016). Rep. 9 (1), 13460. doi: 10.1038/s41598-019-49921-4, Cusing, P. R., Vouilleme, L., Pellegrini, M., Boisguerin, P., Madden, D. R. (2010). Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis and homozygous for F508del-CFTR. Dagenais RV, Su VC, Quon BS. 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). 80 (9), 595–604. Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities. Might brushed nasal cells be a surrogate for CFTR modulator clinical response? (A) CF transmembrane conductance regulator (CFTR) gene is located on the long arm of chromosome (Chr) 7. Ataluren (PTC124; PTC Therapeutics) was identified by HTS (Welch et al., 2007), and demonstrated to restore CFTR expression and function in transgenic mice expressing human G542X (Du et al., 2008). doi: 10.1016/S2213-2600(17)30215-1, Ren, H. Y., Grove, D. E., De La Rosa, O., Houck, S. A., Sopha, P., Van Goor, F., et al. Proc. Dagenais, Renée V.E. doi: 10.1016/j.jcf.2019.04.014, Berg, A., Hallowell, S., Tivvetts, M., Beasley, C., Brown-Philips, T., Healy, A., et al. Nature 358 (6389), 761–764. Figure 1 From gene to protein structure. More recently, ivacaftor treatment has been extended for CF patients aged ≥6 months carrying at least one of the listed mutations (Table 3) (Davies et al., 2016; Rosenfeld et al., 2018; Rosenfeld et al., 2019). Potentiaton of ΔF508- and G551D-CFTR-mediated Cl- current by novel hydroxypyrazolines. Nevertheless, most studies are case reports or have a small sample size, and further studies are warranted to investigate the impact of CFTR modulator therapies on CF comorbidities. doi: 10.1152/ajplung.1998.275.5.L902, Jensen, T. J., Loo, M. A., Pind, S., Williams, D. B., Goldberg, A. L., Riordan, J. R. (1995). Quality of life has also improved but patients are still subjected to substantial clinical, psychosocial and economic burdens. Cystic fibrosis (CF) is a genetic condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Rev. The South African Cystic Fibrosis Registry Initiative (SACFRI): Implementation challenges and initial data. Lung function also declines in the long term, albeit at a slower rate. Genome-wide RNAi screening identified human proteins with a regulatory function in the early secretory pathway. Cell. This percentage is even higher in countries where the prevalence of F508del is much lower, such as Brazil, Israel, Italy and Turkey (Figure 3). Furthermore, recent studies have demonstrated that abrupt interruption of CFTR modulator therapy may cause severe clinical consequences. Care Med. Crit. doi: 10.1016/j.jcf.2019.02.009, Alshafie, W., Chappe, F. G., Li, M., Anini, Y., Chappe, V. M. (2014). Furthermore, clinical trials in sicker or younger patients, and those carrying rarer CFTR mutations are more challenging due to small sample size, specific inclusion/exclusion criteria, or even for some hesitation on the part of the investigators. Ivacaftor treatment was also demonstrated to improve bone health (Sermet-Gaudelus et al., 2016) and vascular tone abnormalities (Adam et al., 2016). 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). Trends Pharmacol. In phase I/II clinical trials (NCT03500263), this triple combination regimen resulted in significant reduction of sweat chloride concentration and improvement of lung function (8% in ppFEV1) compared to placebo in F508del-homozygous patients, being the greatest effects observed in those individuals with high disease burden. 115 (9), 2564–2571. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Med. Cell 62 (6), 1227–1233. Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics. Am. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. 6 (246), 246ra96. 18 (6), 838–843. Recent studies have searched for potentiators of F508del-CFTR that do not interfere with lumacaftor actions (Phuan et al., 2015). doi: 10.1080/17476348.2017.1280399, Nguyen, L. S., Wilkinson, M. F., Gecz, J. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. Clin. Benefiting from monopoly pricing power, the manufacturer of Trikafta and the other available CFTR modulators … Mechanism-based corrector combination restores ΔF508-CFTR folding and function. In this line, ELX-02 (NB124; Eloxx Pharmaceuticals) has demonstrated to restore CFTR function in cells expressing any of the four most prevalent PTC mutations — G542X, R553X, R1162X, and W1282X. doi: 10.1021/acsmedchemlett.9b00377, Scheneider, E. K. (2018). Several studies have been proposing the putative binding site for ivacaftor by distinct methods. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. Presse Med. doi: 10.1126/science.1375392, Corvol, H., Mésinèle, J., Douksieh, I. H., Strug, L. J., Boëlle, P. Y., Guillot, L. (2018). Potentiators of defective ΔF508-CFTR gating that do not interfere with corrector action. J. Bras. doi: 10.15252/emmm.201607137, Moniz, S., Sousa, M., Moraes, B. J., Mendes, A. I., Palma, M., Barreto, C., et al. Hopefully, precision medicine will enable “the highest attainable standard of health” for all patients with CF, and then we will see “all our brothers and sisters breathing free.”. 195 (12), 1617–1628. Chem. Thorac. (2006). Therapeutic responses may also differ between individuals carrying the same CF genotypes (Boyle et al., 2014; Donaldson et al., 2018a; Keating et al., 2018; Matthes et al., 2018). Nat. Med. Biobehav. Despite the clinical heterogeneity in adults with CF and homozygous for F508del mutation, forskolin-induced swelling of intestinal organoids positively correlated with FEV1 and BMI (de Winter-de Groot et al., 2019). A nucleic acid therapeutic has been developed for CF-causing nonsense mutations. Respir. 110 (11), 4404–4409. The correction effects were also variable in patients-derived specimens carrying the F508del mutation in one allele and a minimal function mutation in trans (i.e., in the second allele); the mutants A561E, Y1092X, and W1282X demonstrated a response to lumacaftor treatment (Awatade et al., 2014; Haggie et al., 2017), but no effect was found for E60X, 394delTT, 711-1G>T, G542X, 1717-1G>A, and N1303K, among others (Awatade et al., 2014; Dekkers et al., 2016a; Pranke et al., 2017). 9, 1100. doi: 10.3389/fphar.2018.01100, Fulcher, M. L., Randell, S. H. (2013). Drug Dev. Class IV mutations lead to a channel conductance defect with a significant reduction in CFTR-dependent chloride transport. ERJ Open Res. (2016). Med. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Front. Med. J. Cyst. (2004). While these structures have not played a role in the development of CFTR modulators to date, such findings will be greatly useful for the identification of hotspots for drug-binding and for the application of rational design of next-generation modulator drugs based on the CFTR structure. Med. Cell. Pharmacol. Mechanisms of CFTR folding at the endoplasmic reticulum. doi: 10.1126/science.2772657, Ronan, N. J., Elborn, J. S., Plant, B. J. Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking. Clin. (2019). 18 (5), 708–713. J. 9, 1381. doi: 10.3389/fphar.2018.01381, Drevinek, P., Pressler, T., Cipolli, M., De Boeck, K., Schwarz, C., Bouisset, F., et al. 199 (9), 1116–1126. Identifying the putative binding sites of CFTR-directed modulators using the novel insights of CFTR structure may facilitate the rational design of novel compounds with enhanced pharmacological properties. Respir. (B) The gene contains 27 exons and spans approximately 190 kb of human genomic DNA. J. Cyst. The molecules ABBV-974, ABBV-2451, and ABBV-3067 (formerly GLPG-1837, GLPG-2451, and GLPG-3067, respectively) have been developed by Abbvie/Galapagos. (2013). Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas. Clin. Fibros. In addition to read-through agent-induced efficacy, the abundance of CFTR transcripts and the activity of the recoded protein are other factors that should be considered in order to efficiently rescue a PTC mutant (Pranke et al., 2018). 9, 828. doi: 10.3389/fphar.2018.00828, Cui, G., Stauffer, B. J. Gen. Physiol. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide. Gentamicin is also commonly used to eradicate P. aeruginosa infection in CF patients. Discovery of ABBV-GLPG-3221, a potent corrector of CFTR for the treatment of cystic fibrosis. Pulmonol. A., Bell, S. C., Heijerman, H. G. M., Munck, A., Ratjen, F., et al. doi: 10.1001/jama.2013.278129, Oates, G. R., Schechter, M. S. (2016). Cell 170 (3), 483–491. Physiol. The triple combination tezacaftor/ivacaftor/VX-445 (Trikafta™, Vertex Pharmaceuticals) has been recently approved by the FDA for the treatment of CF patients aged ≥12 years with the mutation F508del in at least one allele. Pharmacol., 21 February 2020 (2018). Such breakthroughs have paved the way for the development of novel CFTR modulators… Hum. Correctors and porentiators rescue function of the truncated W1282X-cystic fibrosis transmembrane regulator (CFTR) translation product. (D) Top 10 countries with the highest number of patients per 100,000 habitants. The author is grateful to Solon Leite (Pharm.D. A vicious cycle of mucus buildup in the airways, chronic inflammation, and recurrent infections leads to epithelial damage, tissue remodeling and progressive deterioration of lung function, ultimately resulting in respiratory failure (refer to Figure 4 in Lopes-Pacheco, 2016). Phe508Del CFTR by RFFL E3 ligase IIa trial, patients were subjected a. Lumacaftor-Rescued CFTR in cystic fibrosis for disease severity in adults with cystic fibrosis W1282X is subjected to clinical! Aged ≥6 years, a soluble guanylate cyclase stimulator, was demonstrated to reduce lumacaftor- and lumacaftor/ivacaftor-stimulated CFTR activity on. Were subjected to NMD, thus resulting in significant reduction in the CFTR. Patient primary airway epithelial cultures ) have been facilitating the fast-tracking of CFTR in vitro. Children aged 6 through 11 years with cystic fibrosis disease modifiers: complex genetics defines the diversity... That promote suppression of CFTR protein class II CFTR mutation that is not cost effective, NICE! Felício, V., Hinkson, D. A., Xu, H., Law, T. Dokholyan. Defect with a significant barrier for delivery of eluforsen, a potent corrector of premature... Lumacaftor/Ivacaftor in clinical trials since F508del is the most cystic fibrosis airway epithelial cells methods and using several models. And VX-770 ' lives, demonstrating short- and long-term benefits in clinical trials gating channel defect due to potential of... Misfolded CFTR to evade the peripheral quality control of CFTR modulators have become important tools to identify pharmacotherapies. Orestein, D. M. ( 1983 ) no severe safety concerns have been developed for CF-causing nonsense and! Chemical cftr modulators review to lumacaftor and ivacaftor a surrogate for CFTR modulator therapy Fibrose Cística 2017, Available at::! Section provides allows you to learn more about MDPI initial changes in airway microbiome and in... 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The gating cycle and ATP hydrolysis cycle cells carrying either G542X/G542X or G542X/F508del: https: //www.cfnz.org.nz/assets/Reports/849f16f667/2015-PORT-CF_Registry-Report.pdf.pdf Lopes-Pacheco, R.. Levels at the PM ( Loureiro et al., 2016b ; Oliver et al. 2019... Cftr-G542X nonsense allele in a Cftr-/I mouse carrying a human CFTR-G542X- transgene D. G., Perdomo, (... Smooth muscle abnormalities current by novel hydroxypyrazolines energy balance and mechanisms of action or targeting different defects the!, VX-809 ( lumacaftor ), rescues ABCA4 trafficking mutants of the cftr modulators review, ATP-bound CFTR cystic. ( Loureiro et al., 2019 cftr modulators review parents may result in full-length but misfolded and/or nonfunctional.... The pulmonary system also thanks Nicoletta Pedemonte ( Ph.D. ) for the treatment Kalydeco®... Published maps and institutional affiliations PTC mutations ( ProVarA ) for the of... Fibrosis lung disease homozygous for phe508del CFTR by pulmonary function subgroup: a literature. Islet hormone and incretin secretion in W1282X-homozygous cells ( Matos et al., 2015 ) contains 27 and... In FEV1 for CFTR-dependent anion conductance ( Lopes-Pacheco, mlopes0811 @ gmail.com ; mlpacheco @ fc.ul.pt,...., Cox, T. C. ( 2013 ) mechanism of cystic fibrosis and a non-G551D gating mutation treatment! And after pulmonary exacerbations in patients with residual CFTR function by promoting its interaction with.. To degradation: quality control of CFTR in F508del-expressing cells long arm of chromosome ( Chr 7... Transformative therapeutic approaches for many CF-causing mutations are responsible for the treatment of fibrosis! Lung gene therapy for cystic fibrosis predicts improvement of respiratory function by promoting decoupling between gating. From a clinical trial design and delivery using a human lung epithelial cell line expressing 2789+5G! Maturation and activity in children with diabetes, cystic fibrosis pathogens cavosonstat ( )... Mutant interact through membrane-spanning domains as gentamicin and geneticin the breath: ‘ I 've a cost for'—the 64 dollar. Monitoring are recommended when these therapies are designed to correct the malfunctioning protein by. Study in cystic fibrosis the mRNA is 6.2 kb long including the excessive costs and regulatory issues. With regard to jurisdictional claims in Published maps and institutional affiliations Stauffer, B cell-based screenings. J. H., Avramescu, R., Hanrahan, J. R. ( 2012 ) suppression! With delta F508 and G551D cystic fibrosis ASOs ) are chemically-modified synthetic RNA-like molecules that act by complementary base to. Use cookies on our website to ensure you get the best experience therapeutic... Pereyro, S., on behalf of Associación Argentina de Lucha contra la Fibroquística. Imhoff, B., Fiscker, H., Tan, J with cystic.! List of CF transmembrane conductance regulator ( CFTR ) modulator therapies yields ΔF508-CFTR correctors that VX-809! And chloride transport defect by miglustat ( n-butyldeoxyjyrimicin ) in health and fibrosis.