Cell. ; Su, Victoria C.H. doi: 10.1016/j.cell.2017.02.024, Liu, F., Zhang, Z., Levit, A., Levring, J., Touhara, K. K., Shoichet, B. K., et al. Sci. Pharmacol. Angew. Infect. Even for F508del-homozygous patients, co-treatment with lumacaftor/ivacaftor resulted in significant but variable clinical responsiveness (Boyle et al., 2014; Wainwright et al., 2015). doi: 10.1165/rcmb.2018-0316OC, Kelly, A., De Leon, D. D., Sheikh, S., Cambum, D., Kubrak, C., Peleckis, A. J., et al. Am. Defective intracellular transport and processing of CFTR is the molecular basis of the most cystic fibrosis. (1991). Cystic fibrosis: breakthrough drugs at break-the-bank prices. Measurements of functional responses in human primary lung cells as a basis for personalized therapy for cystic fibrosis. Sci. Such findings denote the relevance of assessing the drug effectiveness at an individual level in patient-derived specimens. Am. Chappe, V., Hinkson, D. A., Zhu, T., Chang, X. Conformation changes of CFTR upon phosphorylation and ATP binding. Sci. (1995). It was also highly functional in primary bronchial epithelial cells from a F508del-homozygous patient (Wang et al., 2018; Singh et al., 2019). doi: 10.1164/rccm.201601-0154OC, Mutyam, V., Libby, E. F., Peng, N., Hadjiliadis, D., Bonk, M., Solomon, G. M., et al. In experimental studies, RCT101 demonstrated an increase in CFTR-dependent chloride secretion in primary bronchial epithelial cells carrying either G542X/G542X or G542X/F508del. Sci. Providing educational and supporting approaches to young children and their parents may result in optimal, lifelong treatment adherence. Clin. doi: 10.3310/hta18180, Wilschanski, M., Zielenski, J., Markiewicz, D., Tsui, L. C., Corey, M., Levison, H., et al. Sci. (2017). Rep. 9 (1), 7234. doi: 10.1038/s41598-019-43652-2, Haggie, P. M., Phuan, P. W., Tan, J. 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. doi: 10.1146/annurev-genom-083117-021329, O'Sullivan, B. P., Orenstein, D. M., Milla, C. E. (2013). 61 (4), 1425–1435. Crit. doi: 10.1083/jcb.200312018, Sharma, D., Xing, S., Hung, Y. T., Caskey, R. N., Dowell, M. L., Touchette, D. R. (2018). Ther. doi: 10.1016/j.jcf.2019.05.015, Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., et al. doi: 10.1056/NEJMoa1105185, Rapino, D., Sabirzhanova, I., Lopes-Pacheco, M., Grover, R., Guggino, W. B., Cebotaru, L. (2015). Soc 16 (11), 1375–1382. 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). Chem. (2018). 12 (9), 548–555. Such findings might partially explain the modest efficacy observed in co-treatment with lumacaftor/ivacaftor in clinical trials. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. (2019). 270 (5 Pt 1), 1544–1555. Furthermore, drug repurposing may unravel effective therapies for patients with common and rare CF-causing mutations in an expedited way and at a feasible cost for national healthcare systems. (2016a). doi: 10.1016/S2213-2600(14)70218-8, McNamara, J. J., McColley, S. A., Marigowda, G., Liu, F., Tian, S., Owen, C. A., et al. This is an early access version, the complete PDF, HTML, and XML versions will be available soon. Might brushed nasal cells be a surrogate for CFTR modulator clinical response? 4 (8), 617–626. 151 (7), 912–928. J. Cyst. doi: 10.1172/JCI124282, Orestein, D. M., O'Sullivan, B. P., Quinton, P. M. (2015). (2019). J. Respir. J. Physiol. Lancet Respir. Table 3 List of CF transmembrane conductance regulator (CFTR) mutations eligible for the treatment with Kalydeco® and Symdeko®/Symkevi®. Science 256 (5058), 774–779. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies. Discuss which patients are candidates for CFTR modulators and what short- and long … Mechanism-based corrector combination restores ΔF508-CFTR folding and function. 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. Cell. 5 (7), 557–567. The cystic fibrosis airway milieu enhances rescue of F508del in a pre-clinical model. The development of CFTR modulators has led to a new era in the treatment of cystic fibrosis (CF), changing the focus of therapy from managing the symptoms of CF to addressing the root cause of the … Lancet Respir. To date, four CFTR modulators have reached the market for the treatment of patients carrying specific CF-causing mutations and these breakthroughs have paved the way for the development of novel pharmacotherapies, which are currently under experimental and clinical investigations. Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. Transl. doi: 10.1164/rccm.201906-1227OC, Bush, A., Simmonds, N. J. Ivacaftor is on the market for over 7 years, and it is transforming patients' lives with sustained and long-term benefits, including reduction in sweat chloride to normal levels, slower deterioration of lung function, reduction in the number of pulmonary exacerbation episodes, less frequent detection of Pseudomonas aeruginosa (McKone et al., 2014; Heltshe et al., 2015) and other common pathogens (Frost et al., 2019), better body mass index (BMI) (Borowitz et al., 2016), exercise capacity and well-being (Edgeworth et al., 2017), and quality of life (Quittner et al., 2015; Sawicki et al., 2015). The CFTR mRNA translates into a 1,480-amino acid protein. Invest. 22 (2), 187–191. Int. Pediatr. Med. Nevertheless, as CF patients are already subjected to a substantial burden of medications, drug-drug interaction profiles should be further exploited to avoid adverse effects or inhibitory effects of one therapy on another. (2018). Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies. Pharmacokinetic and drug-drug interaction profiles of the combination of tezacaftor/ivacaftor. Exp. Furthermore, these ASOs increased CFTR-dependent chloride secretion in W1282X-homozygous cells (Keenan et al., 2019). (2016). Front. Biol. A significant, albeit modest, improvement in lung function (3%–4% in ppFEV1) was found only when lumacaftor was co-administered with ivacaftor in a following clinical trial (Boyle et al., 2014). 4 (6), 8–9. Chem. doi: 10.1172/jci.insight.98699, Tosco, A., De Gregorio, F., Esposito, S., De Stefano, D., Sana, I., Ferrari, E., et al. Mutations in classes I, II, and III are usually associated with a classical and more severe disease, while those in classes IV, V, and VI are related to milder (or atypical) phenotypes. The author is grateful to Solon Leite (Pharm.D. Pediatr. 8 (344), 344ra84. doi: 10.1074/jbc.274.31.21873, Habib, A. R., Kajbafzadeh, M., Desai, S., Yang, C. L., Skolnik, K., Quon, B. S. (2019). Acad. doi: 10.1016/j.jcf.2017.01.009, Donaldson, S. H., Pilewski, J. M., Griese, M., Cooke, J., Viswanathan, L., Tullis, E., et al. In developed countries, certain health authorities have also been slow in approving reimbursement (Bush and Simmonds, 2012; Whiting et al., 2014; Sharma D. et al., 2018) and the cost-effectiveness of these pharmacotherapies has yet been questioned (Gulland, 2016; Balk et al., 2018). Med. Although CF is a multi-organ disease, the respiratory disorder represents the major cause of morbidity and mortality of these patients. Theranostics by testing CFTR modulators in patients-derived materials: The current status and a proposal for subjects with rare CFTR mutations. As approved drugs have already undergone extensive toxicological evaluations in both experimental and early-stage clinical studies, the time frame to obtain a new disease indication may be reduced, if safety and efficacy is demonstrated for the repurposed use in late-stage clinical studies (Pushpakom et al., 2019). Fibros. doi: 10.1007/s00018-016-2391-y, Sampson, H. M., Robert, R., Liao, J., Matthes, E., Carlile, G. W., Hanrahan, J. W., et al. Int. J. Clin. Zeitlin, P. L., Diener-West, M., Rubenstein, R. C., Boyle, M. P., Lee, C. K., Brass-Ernst, L. (2002). J. Mol. Eur. Nature 447 (7140), 87–91. Another system has also been proposed to take into account the pleiotropic defects of many CFTR mutations, including the F508del (Veit et al., 2016a). J. Med. Assess. JCI Insight 1, e86183. (2017). Combination of correctors rescue ΔF508del-CFTR by reducing its association with Hsp40 and Hsp27. Care Med. These glycans are modified upon traversing the Golgi complex and may interact with extracellular macromolecules when the protein is located at the PM (Glozman et al., 2009; Lukacs and Verkman, 2012). (1989). It binds and potentiates CFTR function by promoting decoupling between ATP hydrolysis and gating cycles (Jih and Hwang, 2013). Proc. Med. (2015). The CFTR-associated ligand arrests the trafficking of the mutant ΔF508 CFTR chnnel in the ER contributing to cystic fibrosis. 9, 1381. doi: 10.3389/fphar.2018.01381, Drevinek, P., Pressler, T., Cipolli, M., De Boeck, K., Schwarz, C., Bouisset, F., et al. Chem. CF affects over 90,000 individuals and they are heterogeneously distributed worldwide (Figure 2). Med. Correction of a cystic fibrosis splicing mutation by antisense oligonucleotides. A clinical trial has also evaluated the effects of lumacaftor/ivacaftor in patients carrying A455E in at least one allele (NCT03061331), since this mutation has demonstrated an increase in CFTR PM abundance and function after corrector treatments in cell models (Dekkers et al., 2016a; Dekkers et al., 2016b; Lopes-Pacheco et al., 2016). Am. 10 (11), 1543–1548. Peripheral protein quality control as a novel drug target for CFTR stabilizer. Nature 354 (6354), 526–528. Eur. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators … 17 (5), 595–606. Although certain CFTR mutants are functional and present at the PM, the protein may still display a significant reduction in half-life (Haardt et al., 1999) (Class VI, Figure 4), probably due to accelerated endocytosis (Swiatecka-Urban et al., 2005) and/or reduced recycling (Sharma et al., 2004). (2019). 4 (2), 91–92. Nat. Lancet Respir. Med. doi: 10.1016/j.jcf.2019.02.009, Alshafie, W., Chappe, F. G., Li, M., Anini, Y., Chappe, V. M. (2014). Lancet Respir. (2018). Respir. Cystic Fibrosis New Zealand. (1989). B., Liu, B., Koenig, J. R., Altenbach, R., Gfesser, G. A., et al. Med. Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR. J. Biol. Drug Deliv. A., Bell, S. C., Heijerman, H. G. M., Munck, A., Ratjen, F., et al. ; Quon, B.S. Mol. [Data compiled from the last Patient Registry Report in Argentina (Pereyro et al., 2018), Australia (Cystic Fibrosis Australia, 2018), Brazil (Brazilian Cystic Fibrosis Study Group, 2019), Canada (Cystic Fibrosis Canada, 2019), Europe (European Cystic Fibrosis Society, 2019), New Zealand (Cystic Fibrosis New Zealand, 2019), South Africa (Zampoli et al., 2019), UK (Cystic Fibrosis Trust, 2019), and the USA (Cystic Fibrosis Foundation, 2019)]. doi: 10.1124/mol.115.099689, Phuan, P. W., Son, J. H., Tan, J. doi: 10.1177/2472555217729790, Glozman, R., Okiyoneda, T., Mulvihill, C. M., Rini, J. M., Barriere, H., Lukacs, G. L. (2009). Nat. 25 (2), 675. J. Med. doi: 10.1152/ajplung.00169.2005, Van Goor, F., Hadida, S., Gootenhuis, P. D., Burton, B., Cao, D., Neuberger, T., et al. Table 1 Publications evaluating safety and efficacy and post-approval observational studies of CF transmembrane conductance regulator (CFTR) modulators in CF patients (*). Cell. Care Med. J. Pediatr. Most CF patients carry a mistrafficking CFTR mutation, since F508del is the most prevalent CF-causing mutation (Class II, Figure 4). (2013). The molecule PTI-801 (posenacaftor; Proteostasis Therapeutics) — a third-generation corrector — has demonstrated higher efficacy compared to first- and second-generation correctors (e.g., lumacaftor and tezacaftor) with additive/synergistic effects when they were co-administered in vitro. Understanding the cellular and molecular basis of the disease has paved the way for the development of therapeutic strategies targeting the underlying dysfunctions caused by CF mutations. Adherence to ivacaftor has nevertheless varied from suboptimal (Siracusa et al., 2015) to optimal (Suthoff et al., 2016). ECFS Patient Registry – 2017 Annual Data Report, Available at: https://www.ecfs.eu/sites/default/files/general-content-images/working-groups/ecfs-patient-registry/ECFSPR_Report2017_v1.3.pdf. VIP regulates CFTR membrane expression and function in Calu-3 cells by increasing its interaction with NHERF1 and P-ERM in a VPAC1- and PKCϵ-dependent manner. J. Care Med. Clinical trials in a dish. (2014). Some reports have suggested that lumacaftor has a putative binding site at the interface of NBD1 with the intracellular loop 4 in TMD2 (He et al., 2013; Okiyoneda et al., 2013; Hudson et al., 2017). A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. Mutat. Socio-economic burden of rare diseases: A systematic review of cost of illness evidence. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. Adam, R. J., Hisert, K. B., Dodd, J. D., Grogan, B., Launspach, J. L., Barnes, J. K., et al. doi: 10.1073/pnas.0904709106, Van Goor, F., Hadida, S., Gootenhuis, P. D., Burton, B., Stack, J. H., Straley, K. S., et al. Transl. doi: 10.1242/jcs.185629, Loo, T. W., Clarke, D. M. (2017). doi: 10.1590/1678-4685-gmb-2018-0148, Middleton, P. G., Mall, M. A., Drevínek, P., Lands, L. C., McKone, E. F., Polineni, D., et al. Nat. 197 (2), 214–224. (2018). Health Technol. Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. They result from alternative splicing, promoter or missense mutations. doi: 10.1016/j.jcf.2018.10.015, Shakkottai, A., Kidwell, K. M., Townsend, M., Nasr, S. Z. (2017). Med. A., Calucho, M., Pereira, L., et al. doi: 10.1007/s00109-011-0787-6, Rowe, S. M., Heltshe, S. L., Gonska, T., Donaldson, S. H., Borowitz, D., Gelfond, D., et al. *Clinical development has been discontinued. (2019). J. Respir. Dis. Other common mutations that cause such abnormality are the G85E, I507del, R560T, and N1303K (found in 0.4%, 0.5%, 0.2%, and 1.6% CF alleles, respectively) (CFTR2 Database). Genistein is an isoflavone that binds to and inhibits protein-tyrosine kinase, resulting in increased intracellular cAMP levels, which leads to potentiation of CFTR activity in cell models (Illek and Fischer, 1998). 14 (5), 621–626. 56, 344. doi: 10.1001/archpedi.1938.01980140114013, Angelis, A., Tordrup, D., Kanavos, P. (2015). Am. doi: 10.1016/S2213-2600(14)70132-8. (2015). Child. 46 (Pt 2), 175–186. Class IV mutations lead to a channel conductance defect with a significant reduction in CFTR-dependent chloride transport. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. The molecules FDL169 and FLD1737 have been investigated by Flatley Discovery Lab. ABBV-2222 (or galicaftor) has a similar chemical structure to lumacaftor and tezacaftor but was reported to be more potent. Sci. Rectal organoids enable personalized treatment of cystic fibrosis. JCI Insight 3 (3), e98699. ABBV-2737 was demonstrated to rescue functional expression of CFTR in F508del-expressing cells, and such effects were enhanced when it was co-administered with lumacaftor or ABBV-2222 (de Wilde et al., 2019). doi: 10.1007/s10620-015-3834-2, Boucher, R. C., Stutts, M. J., Knowles, M. R., Cantley, L., Gatzy, J. T. (1986). Fibros. Ataluren (PTC124) induced cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. J. Respir. doi: 10.1164/rccm.201405-0882LE, Hayes, D., Jr., Kopp, B. T., Hill, C. L., Lallier, S. W., Schwartz, C. M., Tadesse, M., et al. 14 (1), 16–25. doi: 10.1159/000475578, Lopes-Pacheco, M., Kitoko, J. Sci. (2015). In F508del-heterozygous patients, the triple combination PTI-428/PTI-808/PTI-801 demonstrated a more variable change in sweat chloride concentration and lung function. doi: 10.1021/acs.jmedchem.7b01339, Welch, E. M., Barton, E. R., Zhuo, J., Tomizawa, Y., Friesen, W. J., Trifillis., P., et al. Reduced histone deacetylase 7 activity function to misfolded CFTR in cystic fibrosis. PloS Biol. The author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 377 (21), 2013–2023. Patients with CFhave mutations in the CFTR gene, which is supposed to create a protein thatregulates the flow of water and chloride in and out of the cells that line thelungs, pancreas, and other organs. Although there are some archaic references regarding “children whose brow had salty taste when kissed and prematurely died”, CF remained uncharacterized until the 1930s. In a phase I trial, PTI-801 was demonstrated to significantly reduce sweat chloride concentration, and improve ppFEV1 and BMI in F508del-homozygous patients receiving lumacaftor/ivacaftor therapy. The NBDs present highly conserved sequence for ATP binding and hydrolysis, while the RD is highly disordered and has multiple consensus sequences containing serines and threonines for phosphorylation by protein kinase A (PKA) and protein kinase C (PKC). A., Xu, H., Avramescu, R. G., Perdomo, D., et al. J. Mol. Crit. J. J. Respir. doi: 10.1124/mol.118.111799, Leonard, A., Lebecque, P., Dingemanse, J., Leal, T. (2012). doi: 10.1093/cid/ciu944, Hisert, K. B., Heltshe, S. L., Pope, C., Jorth, P., Wu, X., Edward, R. M., et al. By current modulators 2003 ) with gating mutations model for ototoxicity ( Xue et al., 2019 ) from... In younger children than replacing some symptomatic therapies might appear less attractive symptomatic therapies 2017.. Being developed in collaboration between pharmaceutical companies and academic laboratories of tezacaftor/ivacaftor accounts approximately... 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