Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids

O’Sullivan, 2009, Cystic fibrosis, Lancet, 373, 1891, 10.1016/S0140-6736(09)60327-5 Kuk, 2015, Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects, Ther. Adv. Respir. Dis., 9, 313, 10.1177/1753465815601934 Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N. Engl. J. Med., 365, 1663, 10.1056/NEJMoa1105185 Accurso, 2010, Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation, N. Engl. J. Med., 363, 1991, 10.1056/NEJMoa0909825 Davies, 2013, Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation, Am. J. Respir. Crit. Care Med., 187, 1219, 10.1164/rccm.201301-0153OC Rowe, 2014, Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis, Am. J. Respir. Crit. Care Med., 190, 175, 10.1164/rccm.201404-0703OC Wainwright, 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N. Engl. J. Med., 373, 220, 10.1056/NEJMoa1409547 Riordan, 1989, Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA, Science, 245, 1066, 10.1126/science.2475911 Rommens, 1989, Identification of the cystic fibrosis gene: chromosome walking and jumping, Science, 245, 1059, 10.1126/science.2772657 Mayer, 2016, Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the ‘breakthrough’, Evid. Based Med., 21, 83, 10.1136/ebmed-2015-110325 Dekkers, 2016, Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis, Sci. Transl. Med., 8, 10.1126/scitranslmed.aad8278 Bose, 2019, Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR, Am. J. Physiol. Lung Cell Mol. Physiol, 10.1152/ajplung.00034.2019 Veeze, 1991, Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis, Gastroenterology, 101, 398, 10.1016/0016-5085(91)90017-F Okiyoneda, 2013, Mechanism-based corrector combination restores DeltaF508-CFTR folding and function, Nat. Chem. Biol., 9, 444, 10.1038/nchembio.1253 Dekkers, 2013, A functional CFTR assay using primary cystic fibrosis intestinal organoids, Nat. Med., 19, 939, 10.1038/nm.3201 Chen, 2018, Pluripotent stem cell platforms for drug discovery, Trends Mol. Med., 24, 805, 10.1016/j.molmed.2018.06.009 Clevers, 2016, Modeling development and disease with organoids, Cell, 165, 1586, 10.1016/j.cell.2016.05.082 Fatehullah, 2016, Organoids as an in vitro model of human development and disease, Nat. Cell Biol., 18, 246, 10.1038/ncb3312 Lancaster, 2014, Organogenesis in a dish: modeling development and disease using organoid technologies, Science, 345, 10.1126/science.1247125 Veit, 2016, From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations, Mol. Biol. Cell, 27, 424, 10.1091/mbc.e14-04-0935 Sosnay, 2013, Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene, Nat. Genet., 45, 1160, 10.1038/ng.2745 Zhang, 2016, Atomic structure of the cystic fibrosis transmembrane conductance regulator, Cell, 167, 1586, 10.1016/j.cell.2016.11.014 Liu, 2017, Molecular structure of the human CFTR ion channel, Cell, 169, 10.1016/j.cell.2017.02.024 Zhang, 2017, Conformational changes of CFTR upon phosphorylation and ATP binding, Cell, 170, 483, 10.1016/j.cell.2017.06.041 Cheng, 1991, Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel, Cell, 66, 1027, 10.1016/0092-8674(91)90446-6 Cheng, 1990, Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis, Cell, 63, 827, 10.1016/0092-8674(90)90148-8 Dalemans, 1991, Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation, Nature, 354, 526, 10.1038/354526a0 Lukacs, 1993, The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells, J. Biol. Chem, 268, 21592, 10.1016/S0021-9258(20)80582-1 Sharma, 2001, Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments, J. Biol. Chem., 276, 8942, 10.1074/jbc.M009172200 Castellani, 2008, Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice, J. Cyst. Fibros., 7, 179, 10.1016/j.jcf.2008.03.009 Cuppens, 1998, Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation, J. Clin. Invest., 101, 487, 10.1172/JCI639 Clain, 2005, A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype, Hum. Genet., 116, 454, 10.1007/s00439-004-1246-z Baatallah, 2018, Cis variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules, Hum. Mutat., 39, 506, 10.1002/humu.23389 Lucarelli, 2017, A new targeted CFTR mutation panel based on next-generation sequencing technology, J. Mol. Diagn., 19, 788, 10.1016/j.jmoldx.2017.06.002 Ivanov, 2018, Targeted sequencing reveals complex, phenotype–correlated genotypes in cystic fibrosis, BMC Med. Genomics, 11, 13, 10.1186/s12920-018-0328-z van Willigen, 2019, Folding-function relationship of the most common cystic fibrosis–causing CFTR conductance mutants, Life Sci. Alliance, 2, 10.26508/lsa.201800172 Dijkstra, 1994, A novel mutation (G1249R) in exon 20 of the CFTR gene, Hum. Mutat., 4, 161, 10.1002/humu.1380040213 Dujardin, 2011, Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811+1G>C and 1898+3A>G, J. Cyst. Fibros., 10, 212, 10.1016/j.jcf.2010.12.008 Van Goor, 2009, Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770, Proc. Natl. Acad. Sci. U. S. A., 106, 18825, 10.1073/pnas.0904709106 Yu, 2012, Ivacaftor potentiation of multiple CFTR channels with gating mutations, J. Cyst. Fibros., 11, 237, 10.1016/j.jcf.2011.12.005 Jih, 2013, Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle, Proc. Natl. Acad. Sci. U. S. A, 110, 4404, 10.1073/pnas.1215982110 Van Goor, 2014, Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function, J. Cyst. Fibros., 13, 29, 10.1016/j.jcf.2013.06.008 Flume, 2012, Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation, Chest, 142, 718, 10.1378/chest.11-2672 Hudson, 2017, Direct binding of the corrector VX-809 to human CFTR NBD1: evidence of an allosteric coupling between the binding site and the NBD1:CL4 interface, Mol. Pharmacol., 92, 124, 10.1124/mol.117.108373 Ren, 2013, VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1, Mol. Biol. Cell, 24, 3016, 10.1091/mbc.e13-05-0240 Clancy, 2012, Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation, Thorax, 67, 12, 10.1136/thoraxjnl-2011-200393 Boyle, 2014, A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial, Lancet Respir. Med., 2, 527, 10.1016/S2213-2600(14)70132-8 Davies, 2018, VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles, N. Engl. J. Med., 379, 1599, 10.1056/NEJMoa1807119 Keating, 2018, VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles, N. Engl. J. Med., 379, 1612, 10.1056/NEJMoa1807120 Han, 2018, Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators, JCI Insight, 3, 121159, 10.1172/jci.insight.121159 Berkers, 2019, Rectal organoids enable personalized treatment of cystic fibrosis, Cell Rep., 26, 10.1016/j.celrep.2019.01.068 de Winter-de Groot, 2018, Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function, Eur. Respir. J., 52, 10.1183/13993003.02529-2017 Zhang, 2015, Off-target effects in CRISPR/Cas9–mediated genome engineering, Mol. Ther. Nucleic Acids, 4, e264, 10.1038/mtna.2015.37 Esser, 2017, Structures of the multidrug transporter P-glycoprotein reveal asymmetric ATP binding and the mechanism of polyspecificity, J. Biol. Chem., 292, 446, 10.1074/jbc.M116.755884 Kim, 2018, Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation, Science, 359, 915, 10.1126/science.aar7389 Van Goor, 2011, Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809, Proc. Natl. Acad. Sci. U. S. A., 108, 18843, 10.1073/pnas.1105787108 Rabeh, 2012, Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function, Cell, 148, 150, 10.1016/j.cell.2011.11.024 Loo, 2017, Corrector VX-809 promotes interactions between cytoplasmic loop one and the first nucleotide-binding domain of CFTR, Biochem. Pharmacol., 136, 24, 10.1016/j.bcp.2017.03.020 Sinha, 2015, Capturing the direct binding of CFTR correctors to CFTR by using click chemistry, Chembiochem, 16, 2017, 10.1002/cbic.201500123 Veit, 2018, Structure-guided combination therapy to potently improve the function of mutant CFTRs, Nat. Med., 24, 1732, 10.1038/s41591-018-0200-x Brewington, 2018, Generation of human nasal epithelial cell spheroids for individualized cystic fibrosis transmembrane conductance regulator study, J. Vis Exp, 134, e57492 Guimbellot, 2017, Nasospheroids permit measurements of CFTR-dependent fluid transport, JCI Insight, 2, 95734, 10.1172/jci.insight.95734 Raraigh, 2018, Functional assays are essential for interpretation of missense variants associated with variable expressivity, Am. J. Hum. Genet., 102, 1062, 10.1016/j.ajhg.2018.04.003 McCague, 2019, Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis, Am. J. Respir. Crit. Care Med., 199, 1116, 10.1164/rccm.201901-0145OC Lingam, 2017, Investigation of the effects of the CFTR potentiator ivacaftor on human P–glycoprotein (ABCB1), Sci. Rep., 7, 17481, 10.1038/s41598-017-17773-5 Zhang, 2014, Effects of curcumin on ion channels and transporters, Front. Physiol., 5, 94, 10.3389/fphys.2014.00094 Egan, 2004, Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects, Science, 304, 600, 10.1126/science.1093941 Wang, 2007, Curcumin opens cystic fibrosis transmembrane conductance regulator channels by a novel mechanism that requires neither ATP binding nor dimerization of the nucleotide-binding domains, J. Biol. Chem., 282, 4533, 10.1074/jbc.M609942200 Lin, 2016, Synergistic potentiation of cystic fibrosis transmembrane conductance regulator gating by two chemically distinct potentiators, ivacaftor (VX-770) and 5-nitro-2-(3-phenylpropylamino) benzoate, Mol. Pharmacol., 90, 275, 10.1124/mol.116.104570 Phuan, 2014, Synergy-based small-molecule screen using a human lung epithelial cell line yields DeltaF508-CFTR correctors that augment VX-809 maximal efficacy, Mol. Pharmacol., 86, 42, 10.1124/mol.114.092478 Shcheynikov, 2004, Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-), J. Biol. Chem., 279, 21857, 10.1074/jbc.M313323200 Linsdell, 1997, Permeability of wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels to polyatomic anions, J. Gen. Physiol., 110, 355, 10.1085/jgp.110.4.355 Poulsen, 1994, Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator, Proc. Natl. Acad. Sci. U. S. A., 91, 5340, 10.1073/pnas.91.12.5340 Shah, 2016, Airway acidification initiates host defense abnormalities in cystic fibrosis mice, Science, 351, 503, 10.1126/science.aad5589 Shamsuddin, 2019, Concurrent absorption and secretion of airway surface liquids and bicarbonate secretion in human bronchioles, Am. J. Physiol. Lung Cell Mol. Physiol., 316, L953, 10.1152/ajplung.00545.2018 Jung, 2014, Role of calcium signaling in epithelial bicarbonate secretion, Cell Calcium, 55, 376, 10.1016/j.ceca.2014.02.002 Park, 2010, Dynamic regulation of CFTR bicarbonate permeability by Cl-i and its role in pancreatic bicarbonate secretion, Gastroenterology, 139, 620, 10.1053/j.gastro.2010.04.004 Pibiri, 2015, Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives, Eur J. Med. Chem., 101, 236, 10.1016/j.ejmech.2015.06.038 Lueck, 2019, Engineered transfer RNAs for suppression of premature termination codons, Nat. Commun., 10, 822, 10.1038/s41467-019-08329-4 Cooney, 2018, Cystic fibrosis gene therapy: looking back, looking forward, Genes, 9, E538, 10.3390/genes9110538 Vidovic, 2016, rAAV-CFTRDeltaR rescues the cystic fibrosis phenotype in human intestinal organoids and cystic fibrosis mice, Am. J. Respir. Crit. Care Med., 193, 288, 10.1164/rccm.201505-0914OC Merlo, 2003, Modifier genes in cystic fibrosis lung disease, J. Lab. Clin Med., 141, 237, 10.1067/mlc.2003.29 Slieker, 2005, Disease modifying genes in cystic fibrosis, J. Cyst. Fibros., 4, 7, 10.1016/j.jcf.2005.05.006 Collaco, 2008, Update on gene modifiers in cystic fibrosis, Curr. Opin. Pulm. Med., 14, 559, 10.1097/MCP.0b013e3283121cdc Butler, 2015, ENaC inhibitors for the treatment of cystic fibrosis, Pharm. Pat. Anal., 4, 17, 10.4155/ppa.14.51 Shei, 2018, The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis, Curr. Opin. Pharmacol., 43, 152, 10.1016/j.coph.2018.09.007 Moore, 2018, The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease, Expert Opin. Ther. Targets, 22, 687, 10.1080/14728222.2018.1501361 Gorshkov, 2018, Advancing precision medicine with personalized drug screening, Drug Discov. Today, 24, 272, 10.1016/j.drudis.2018.08.010