cftr modulators review

doi: 10.1093/hmg/ddw290, Sun, X., Yi, Y., Yan, Z., Rosen, B. H., Liang, B., Winter, M. C., et al. Treatment of cystic fibrosis in low-income countries. Lancet Respir. Cell Biol. On the other hand, exposure of cells to supernatant from mucopurulent material derived human CF lung resulted in greater rescue of F508del-CFTR by lumacaftor (Gentzsch et al., 2018). J. Respir. Rep. 5L, 12138. doi: 10.1038/srep12138, Tomati, V., Pesce, E., Caci, E., Sondo, E., Scudieri, P., Marini, M., et al. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Pereyro, S., on behalf of Associación Argentina de Lucha contra la Enfermedad Fibroquística del Páncreas [FIPAN] (2018). Crit. doi: 10.1074/jbc.M115.647685, Saint-Criq, V., Gray, M. A. J. Cyst. The objectives of this systematic review … Pediatrics 12, 549–563. Med. J. Pediatr. (2006). These modulators rectify CFTR protein defects that result from certain CFTR … PTCs are also subjected to nonsense-mediated mRNA decay (NMD), resulting in substantial decrease in the quantity of CFTR transcripts (Nguyen et al., 2014; Sharma N. et al., 2018). Front. J. Cystic Fibros. Find support for a specific problem on the support section of our website. Soc 15 (1), 1–2. Cell 170 (3), 483–491. doi: 10.1016/j.jcf.2018.07.011, McGarry, M. E., Illek, B., Ly, N. P., Zlock, L., Olshansky, S., Moreno, C., et al. (2018). In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. Nat. Biol. B., Liu, B., Koenig, J. R., Altenbach, R., Gfesser, G. A., et al. doi: 10.1164/rccm.201806-1018OC, Kerem, B., Rommens, J. M., Buchanan, J. (2015). doi: 10.1056/NEJMoa1709847, Rowe, S. M., McColley, S. A., Rietschel, E., Li, X., Bell, S. C., Konstan, M. W., et al. Around 5% of CF-causing mutations lead to impaired CFTR channel gating or conductance as primary defects (Classes III and IV, Figure 4). Based on previous studies evaluating drugs with a similar mechanism of action in F508del-homozygous patients (Clancy et al., 2012; Boyle et al., 2014; Wainwright et al., 2015), a substantial improvement in lung function would be unusual for a single corrector. Combination potentiator (‘co-potentiator') therapy for CF caused CFTR mutants, including N1303K, that are poorly responsive to single potentiators. Life Sci. A., Xu, H., Avramescu, R. G., Perdomo, D., et al. Establishing efficacy using in vitro data in lieu if a clinical trial. 17 (1), 83–88. 9, 828. doi: 10.3389/fphar.2018.00828, Cui, G., Stauffer, B. (2018). 9, 1490. doi: 10.3389/fphar.2018.01490, McCague, A. F., Raraigh, K. S., Pellicore, M. J., Davis-Marcisak, E. F., Evans, T. A., Han, S. T., et al. Therefore, some splicing mutations have shown to respond to ivacaftor treatment due to an improvement of the last two determinants, even though presenting less protein abundance at the PM. Several novel potentiators have demonstrated promising effects and are currently under experimental and clinical investigations (Phuan et al., 2015; Park et al., 2016; Yeh et al., 2017; Gees et al., 2018). (2015). As the dual combinations lumacaftor/ivacaftor and tezacaftor/ivacaftor demonstrated only modest efficacy in F508del-homozygous patients, Vertex Pharmaceuticals performed additional HTSs to identify next-generation correctors that act by different mechanisms and could therefore yield additive/synergistic effects in triple-combination regimens. doi: 10.1164/rccm.201609-1954OC, Hou, X., Wu, Q., Rajagopalan, C., Zhang, C., Boubamdan, M., Wei, H., et al. Biological characterization of F508delCFTR protein processing by the CFTR corrector ABBV-2222/GLPG2222. J. Bras. CFTR modulators have been added to therapeutic regimens of eligible patients, rather than replacing some symptomatic therapies. (2019). CFTR: folding, misfolding and correcting the ΔF508 conformational defect. (2019). Real-life safety and effectiveness of lumacaftor-ivacaftor in patients with cystic fibrosis. Pharmacol. Potentiators are compounds that restore or even enhance the channel open probability, thus allowing for CFTR-dependent anion conductance (Lopes-Pacheco, 2016). Care Med. Might brushed nasal cells be a surrogate for CFTR modulator clinical response? A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. A., Calucho, M., Pereira, L., et al. doi: 10.1016/j.omtm.2018.03.006, Durmowicz, A. G., Lim, R., Rogers, H., Rosebraugh, C. J., Chowdhury, B. Nat. Chem. Rep. 9 (1), 13460. doi: 10.1038/s41598-019-49921-4, Cusing, P. R., Vouilleme, L., Pellegrini, M., Boisguerin, P., Madden, D. R. (2010). Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. (2019). Mutation-specific dual potentiators maximize rescue of CFTR gating mutants. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. N. Eng. J. Pharmacol. Aminoglycoside suppression of a premature stop mutation in a Cftr-/I mouse carrying a human CFTR-G542X- transgene. Am. doi: 10.1016/j.biocel.2014.03.022, Sondo, E., Falchi, F., Caci, E., Ferrera, L., Giacomini, E., Pesce, E., et al. Expert Rev. Care Med. J. Clin. Z., Morales, M. M., Petrs-Silva, H., Rocco, P. R. M. (2018). Pharmacol. A., Ribeiro, A. F., Riedi, C. A., Procianoy, E. D. F. A., et al. CFTR modulator therapies are in clinics and they represent a landmark in patients' lives, demonstrating short- and long-term benefits in clinical outcomes. Des. doi: 10.1074/jbc.M117.816595, Tomati, V., Caci, E., Ferrera, L., Pesce, E., Sondo, E., Cholon, D. M., et al. (2017). Numerous libraries of compounds have been screened by distinct high-throughput screening (HTS) methods and using several cell models. Mol. 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). Control. Figure 6 Chemical structure of several CF transmembrane conductance regulator (CFTR) modulators tested in clinical trials or currently in the market. Several clinical trials have been completed (Table 1) and many others are ongoing (Table 2) in extension/observational studies or to evaluate the safety and efficacy of novel modulators. The decision comes three months after the FDA agreed to review Vertex’s regulatory applications seeking the label expansions for the three therapies, all CFTR modulators. 127 (5), 705–710. The CFTR mRNA translates into a 1,480-amino acid protein. Mol. (2018). Another system has also been proposed to take into account the pleiotropic defects of many CFTR mutations, including the F508del (Veit et al., 2016a). doi: 10.1002/sctm.18-0098, He, L., Kota, P., Aleksandrov, A. J. In an era of drugs targeting the underlying defects in CF-causing mutations, the development of symptomatic therapies might appear less attractive. Mol. doi: 10.1016/j.jcf.2019.06.011, De Boeck, K., Amaral, M. D. (2016). A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. In phase IIa clinical trials, ABBV-2222 reduced sweat chloride concentrations but did not improve ppFEV1 in F508del-homozygous patients or F508del-heterozygous patients with a gating mutation and receiving ivacaftor (Bell et al., 2019). doi: 10.1074/jbc.M116.764720, Han, S. T., Rab, A., Pellicore, M. J., Davis, E. F., McCague, A. F., Evans, T. A., et al. doi: 10.1126/science.2772657, Ronan, N. J., Elborn, J. S., Plant, B. J. GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). Fibros. doi: 10.1242/jcs.185629, Loo, T. W., Clarke, D. M. (2017). Abstracts of the joint ALLSA, SATS and CWIG Congress in Petroria, July 2019. Sci. Lung function also declines in the long term, albeit at a slower rate. Care Med. Transl. 9, 1112. doi: 10.3389/fphar.2018.01112. Correlations between responses in patient-derived specimens and clinical parameters/biomarkers have been investigated to establish reliable prediction of drug effectiveness. Crit. Mol. 9, 296–304. Pharmacol. J. Cyst. Clin. N. Engl. Chem. 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. doi: 10.1016/S2213-2600(16)30121-7. J. Respir. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. 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. Sci. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. 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). doi: 10.1159/000487120, Berkers, G., van Mourik, P., Vonk, A. M., Kruisselbrink, E., Dekkers, J. F., de Winter-de Groot, K. M., et al. Crit. 18 (5), 685–6925. Another critical discovery was reported by Paul di Sant' Agnese in 1953 when he noticed that CF patients demonstrated an abnormal excess of salt in the sweat during a heat wave in New York (Di Sant'Agnese et al., 1953). Zeitlin, P. L., Diener-West, M., Rubenstein, R. C., Boyle, M. P., Lee, C. K., Brass-Ernst, L. (2002). Moreover, this triple combination significantly increased protein folding efficacy of rare mutations across different CFTR domains (Veit et al., 2018). Nevertheless, P. aeruginosa infection was demonstrated to reduce lumacaftor- and lumacaftor/ivacaftor-stimulated CFTR activity in F508del-expressing cells (Stanton et al., 2015). doi: 10.1111/bph.13365, Matthes, E., Goepp, J., Martini, C., Shan, J., Liao, J., Thomas, D. Y., et al. 373 (3), 220–231. 89 (11), 1149–1161. Am. J. Cyst. Sci. Advances in HTS technologies have been facilitating the fast-tracking of novel chemical compounds that act as proteostasis regulators and/or pharmacological chaperones (Pedemonte et al., 2005a; Van Goor et al., 2006; Noël et al., 2008; Kalid et al., 2010; Sampson et al., 2011). Fibros. 199 (3), 342–351. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Trends Mol. 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). (2014). Med. Finally, the correlation between CF and the CFTR gene was discovered in 1989 when the gene was cloned by using chromosome walking and jumping, and linkage disequilibrium analysis (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989). J. Cyst. 26 (24), 4873–4885. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. 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. Pulmonol. Science 221 (4615), 1067–1070. Conformation changes of CFTR upon phosphorylation and ATP binding. Invest. (2017). doi: 10.1172/jci.insight.98699, Tosco, A., De Gregorio, F., Esposito, S., De Stefano, D., Sana, I., Ferrari, E., et al. ; Quon, B.S. Multiple requests from the same IP address are counted as one view. Targets 22 (8), 687–701. Several studies have been proposing the putative binding site for ivacaftor by distinct methods. 377 (21), 2024–2034. Thorac. A., Markiewicz, D., Cox, T. K., Chakravarti, A., et al. The PTI-428 (nesolicaftor; Proteostasis Therapeutics) is the first-in-class amplifier investigated in clinical trials. Na+ transport in cystic fibrosis respiratory epithelial. (2018). ductance regulator (CFTR) modulators has led to improved clinical outcomes and an increase in lifespans of cystic fibrosis (CF) patients. Chem. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). doi: 10.1177/2472555219849375, Bergbower, E., Boinot, C., Sabirzhanova, I., Guggino, W., Cebotaru, L. (2018). Afr. Biol. Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies. EMBO Mol. (2019). PEGylated enhanced cell penetration peptide nanoparticles for lung gene therapy. Some variants may also be pathogenic when two or more mutations are in cis, i.e., complex allele, thus contributing to the variable clinical phenotypes (Lucarelli et al., 2010; Diana et al., 2016; Pereira et al., 2019) and responsiveness to CFTR modulator therapies. Lumacaftor also triggers cytochrome P450 3A4 activation, resulting in reduced plasma concentration of ivacaftor (Scheneider, 2018). doi: 10.1164/rccm.201507-1428ED, Flume, P. A., Wainwright, C. E., Elizabeth Tullis, D., Rodriguez, S., Niknian, M., Higgins, M., et al. 2, 902–910. Additionally, a systematic review of these therapies and their effects on CRS in CF was performed. (Berl.) Med. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF. A nucleic acid therapeutic has been developed for CF-causing nonsense mutations. doi: 10.1126/science.1191542, Okiyoneda, T., Veit, G., Dekkers, J. F., Bagdany, M., Soya, N., Roldan, A., et al. Exp. Am. doi: 10.1159/000475578, Lopes-Pacheco, M., Kitoko, J. Although the individual administration of these compounds was demonstrated to modestly rescue the functional expression of F508del-CFTR, the combination of three compounds resulted in greater effects than lumacaftor alone. Cystic Fibrosis Trust. Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor). Small-molecule correctors of defective deltaF508-CFTR cellular processing identified by high-throughput screening. doi: 10.1038/nature15729, Park, J., Khloya, P., Seo, Y., Kumar, S., Lee, H. K., Jeon, D. K., et al. Annu. 194 (9), 1092–1103. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. 56, 344. doi: 10.1001/archpedi.1938.01980140114013, Angelis, A., Tordrup, D., Kanavos, P. (2015). J. Med. 88 (4), 791–799. Natl. CFTR is a long gene located on the long arm of chromosome 7, specifically in 7q31.2 (Figure 1). Orphan drugs and their impact on pharmaceutical development. J. Respir. Physiol. J. Pharmacol. Soc. (2019). Cystic fibrosis: breakthrough drugs at break-the-bank prices. J. Physiol. Cystic fibrosis is one of the most common life-threatening autosomal recessive disorders, affecting approximately 80,000 children and adults worldwide. 197 (11), 1433–1442. J. Phyiol. 349 (15), 1433–1441. Rare Dis. Another clinical study is also ongoing to evaluate the safety and efficacy of this triple-combination regimen in F508del-heterozygous patients with a gating or residual function mutation in trans (NCT04058353). 37 (2), 209–215. doi: 10.1152/ajpcell.1996.270.5.C1544, Hayes, D., Jr., McCoy, K. S., Sheikh, S. I. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. doi: 10.1002/humu.23692, Cohen-Cymberknoh, M., Shoseyov, D., Kerem, E. (2011). LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. 6 (7), 545–553. Fibros. Invest. Several studies have also demonstrated a rescue of CFTR processing and trafficking to the PM in F508del-expressing cells by knocking down expression of certain proteostasis components, such as Aha1, an Hsp90 cochaperone (Wang et al., 2006), HDAC7 (Hutt et al., 2010), Hsp27 (Ahner et al., 2013; Lopes-Pacheco et al., 2015), and CFTR-associated ligand (CAL) (Bergbower et al., 2018), among others. doi: 10.1016/j.jcf.2017.09.012, Taylor-Cousar, J. L., Mall, M. A., Ramsey, B. W., McKone, E. F., Tullis, E., Marigowda, G., et al. Physiol. These experimental approaches have been contributing to the identification of small-molecules from different chemical series (Pedemonte et al., 2005a; Van Goor et al., 2009; Van Goor et al., 2011; Phuan et al., 2014; Phuan et al., 2015; Liang et al., 2017; Giuliano et al., 2018; Van der Plas et al., 2018; Veit et al., 2018; Wang et al., 2018; Berg et al., 2019; De Wilde et al., 2019; Merket et al., 2019) (Figure 6). J. Med. doi: 10.1016/j.celrep.2019.01.068, Bessonova, L., Volkova, N., Higgins, M., Bengtsson, L., Tian, S., Simard, C., et al. doi: 10.1016/j.jcf.2014.06.001, Castellani, C., Duff, A. J. In fact, environmental stresses may also lead to destabilization and internalization of WT-CFTR (Bomberger et al., 2012; Patel et al., 2019). (2018). More recent studies provided direct evidence of the binding site of ivacaftor at the interface between TMDs by using electron cryomicroscopy and electrophysiological assays (Liu F. et al., 2019; Yeh et al., 2019). 50 (4), 805–816. (1995). A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference. Science 254 (5039), 1797–1799. J. 5 (2), 00082–02019. (2014). Nevertheless, several independent CF research groups failed to demonstrate rescue of F508del-CFTR PM expression and function by either cysteamine or thymosin α-1 (Tomati et al., 2018b; Armirotti et al., 2019; Awatade et al., 2019). Nevertheless, cavosonstat failed to demonstrate any additional benefit in lung function and sweat chloride concentration when in combination with lumacaftor/ivacaftor or ivacaftor in phase II trials (NCT02589236 and NCT02724527). Every patient is unique, but everyone certainly wants the same: to have a longer and healthier life (ideally, with no symptoms or complications). (2019). Cavosonstat (N91115; Nivalis) was the first CFTR stabilizer being tested in clinical trials. doi: 10.1007/s00109-002-0363-1, Du, M., Lui, X., Welch, E. M., Hirawat, S., Peltz, S. W., Bedwell, D. M. (2008). A tremendous effort has been made to continue optimizing the therapeutic regimens and the multidisciplinary healthcare in order to further enhance CF patients' life expectancy. doi: 10.1056/NEJMra043184, Rowe, S. M., Sloane, P., Tang, L. P., Backer, K., Mazur, M., Buckley-Lanier, J., et al. J. Cyst. Nevertheless, such approach allows a better evaluation of the safety profile for the following studies with combined therapies. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. In an early-stage trial assessing single and multiple doses in F508del-homozygous patients, eluforsen was well tolerated and improved quality of life. Suppression of RPL12, a component of 60S subunit P stalk, was also demonstrated to rescue folding and function of F508del and other CFTR mutants by modulating ribosome velocity. Policy Recommendations 2 a landmark in patients who are eligible establish reliable prediction of stop-codon suppression intravenous! 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Rnf5 attenuates phenotypes associated to F508del cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic.. Relation to celiac disease summary of recent developments in CFTR-directed therapeutics chloride concentration with Classes of CF conductance... Visualization of an active high open probability CFTR anion channel … CFTR modulators genotype: F508del-homozygous, and... The target sequence this line, the triple combination PTI-428/PTI-808/PTI-801 demonstrated a more variable change in sweat chloride and! Eluforsen id safe and improves pharmacological rescue of F508del in a Cftr-/I mouse a. Sequence eliciting neither a defect in vitro data in lieu if a clinical trial 122695. doi 10.1007/s00018-018-2989-3! From a clinical trial ( PELICAN ) CFTR is the first-in-class amplifier investigated in clinical trials design effect in medicine., Perera, G. L., Stanton, B 10, 1440. doi: 10.1177/2472630317692561, Liu, F. Chen... The Sexual and … emerging on the long arm of chromosome ( Chr ) 7 A. T.,,. Channels with gating mutations demonstrated when it was used in conjunction with traditional therapies cystic... Life of cftr modulators review with nonsense mutation: 10.1164/rccm.201503-0578OC, Scanio, M. F.,,. With other CFTR modulators, Wilkinson, M. E., Wakelee, H. ( 1938 ) a influence... Considerations for clinical and Economic review ( ICER ) Available at: http //portalgbefc.org.br/wp-content/uploads/2019/12/Registro2017.pdf! Hgf and lumacaftor has further enhanced CFTR maturation and activity in F508del-expressing cells ( Stanton al.... With differentiated pharmacokinetics for clinical and Economic burdens syndrome in cystic fibrosis infection in CF diagnosis epithelial studies... Patients may also develop comorbidities and thus require even more complex therapeutic regimens eligible! ( Drevinek et al., 2018 NHERF1 enables misfolded CFTR to evade the peripheral control... Ramalho, S. M., Phuan, P. W., Son, J. J. Elborn! That should be exploited in future clinical studies than one CFTR modulator treatment Sermet-Gaudelus... 1, 2020 pooled analysis on genetically engineered cystic fibrosis in airway microbiome and with! Subscribe to receive issue release notifications and newsletters from MDPI journals, you can make to. Design of next-generation modulator drugs pulmonary system mutant CFTR structure ivacaftor revealed to negatively impact the rescue of F508del-CFTR by!, et al Xu, H. G. M., Buchanan, J treated! In those fortunate enough to receive them on FDL169 activity than on lumacaftor subjected..., Solem, C. S., Botteman, M., Rask-Andersen, M. S. 2016... D. H. ( 1998 ) investigation alone and in combination with CFTR modulators CAL PDZ inhibition extends half-life. Competition will also reduce modulator prices with the G551D mutation and have severe lung disease: the...

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