Cystic Fibrosis: New Insights into Therapeutic Approaches

Antonella       Tosco; Valeria    R.    Villella; Valeria       Raia; Guido       Kroemer; Luigi       Maiuri
Abstract

Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over the last few years, new technologies have been developed, and gene editing strategies are now moving toward a one-time cure. This review will summarize recent advances in etiological therapies that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve its function. Moreover, we will discuss how proteostasis regulators can modify the environment in which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.
Keywords: CFTR, cystic fibrosis, gene editing, modulators, precision medicine, repositioning therapy.
Graphical Abstract

[1] 
Elborn JS. Cystic fibrosis. Lancet  2016; 388(10059): 2519-31.
[http://dx.doi.org/10.1016/S0140-6736(16)00576-6] [PMID:  27140670] 
[2] 
Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science  1989; 245(4922): 1066-73.
[http://dx.doi.org/10.1126/science.2475911] [PMID:  2475911] 
[3] 
Meng X, Clews J, Martin ER, Ciuta AD, Ford RC. The structural basis of cystic fibrosis. Biochem Soc Trans  2018; 46(5): 1093-8.
[http://dx.doi.org/10.1042/BST20180296] [PMID:  30154098] 
[4] 
Linsdell P. Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel. Exp Physiol  2006; 91(1): 123-9.
[http://dx.doi.org/10.1113/expphysiol.2005.031757] [PMID:  16157656] 
[5] 
Stephenson AL, Stanojevic S, Sykes J, Burgel PR. The changing epidemiology and demography of cystic fibrosis. Presse Med  2017; 46(6 Pt 2): e87-95.
[http://dx.doi.org/10.1016/j.lpm.2017.04.012] [PMID:  28554720] 
[6] 
Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med  2015; 372(4): 351-62.
[http://dx.doi.org/10.1056/NEJMra1300109] [PMID:  25607428] 
[7] 
Kerem E, Conway S, Elborn S, Heijerman H. Consensus Committee. Standards of care for patients with cystic fibrosis: A European consensus. J Cyst Fibros  2005; 4(1): 7-26.
[http://dx.doi.org/10.1016/j.jcf.2004.12.002] [PMID:  15752677] 
[8] 
Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet  2015; 16(1): 45-56.
[http://dx.doi.org/10.1038/nrg3849] [PMID:  25404111] 
[9] 
Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell  2016; 27(3): 424-33.
[http://dx.doi.org/10.1091/mbc.e14-04-0935] [PMID:  26823392] 
[10] 
Lukacs GL, Verkman AS. CFTR: folding, misfolding and correcting the ΔF508 conformational defect. Trends Mol Med  2012; 18(2): 81-91.
[http://dx.doi.org/10.1016/j.molmed.2011.10.003] [PMID:  22138491] 
[11] 
Okiyoneda T, Barrière H, Bagdány M, et al. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science  2010; 329(5993): 805-10.
[http://dx.doi.org/10.1126/science.1191542] [PMID:  20595578] 
[12] 
Mendoza JL, Schmidt A, Li Q, et al. Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences. Cell  2012; 148(1-2): 164-74.
[http://dx.doi.org/10.1016/j.cell.2011.11.023] [PMID:  22265409] 
[13] 
Balch WE, Roth DM, Hutt DM. Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol  2011; 3(2) a004499
[http://dx.doi.org/10.1101/cshperspect.a004499] [PMID:  21421917] 
[14] 
Pankow S, Bamberger C, Calzolari D, et al. ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature  2015; 528(7583): 510-6.
[http://dx.doi.org/10.1038/nature15729] [PMID:  26618866] 
[15] 
Clancy JP, Cotton CU, Donaldson SH, et al. CFTR modulator theratyping: Current status, gaps and future directions. J Cyst Fibros  2018; pii: S1569-1993(18): 30585-X.
[http://dx.doi.org/10.1016/j.jcf.2018.05.004] 
[16] 
Maiuri L, Raia V, Kroemer G. Strategies for the etiological therapy of cystic fibrosis. Cell Death Differ  2017; 24(11): 1825-44.
[http://dx.doi.org/10.1038/cdd.2017.126] [PMID:  28937684] 
[17] 
Schwank G, Koo BK, Sasselli V, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell  2013; 13(6): 653-8.
[http://dx.doi.org/10.1016/j.stem.2013.11.002] [PMID:  24315439] 
[18] 
Pedemonte N, Zegarra-Moran O, Galietta LJ. High-throughput screening of libraries of compounds to identify CFTR modulators. Methods Mol Biol  2011; 741: 13-21.
[http://dx.doi.org/10.1007/978-1-61779-117-8_2] [PMID:  21594775] 
[19] 
Jennings MT, Flume PA. Cystic fibrosis: Translating molecular mechanisms into effective therapies. Ann Am Thorac Soc  2018; 15(8): 897-902.
[http://dx.doi.org/10.1513/AnnalsATS.201802-075FR] [PMID:  29812963] 
[20] 
Lopes-Pacheco M. CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis. Front Pharmacol  2016; 7: 275.
[http://dx.doi.org/10.3389/fphar.2016.00275] [PMID:  27656143] 
[21] 
Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA  2009; 106(44): 18825-30.
[http://dx.doi.org/10.1073/pnas.0904709106] [PMID:  19846789] 
[22] 
Verkman AS, Galietta LJ. Chloride channels as drug targets. Nat Rev Drug Discov  2009; 8(2): 153-71.
[http://dx.doi.org/10.1038/nrd2780] [PMID:  19153558] 
[23] 
Kalid O, Mense M, Fischman S, et al. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. J Comput Aided Mol Des  2010; 24(12): 971-91.
[http://dx.doi.org/10.1007/s10822-010-9390-0] [PMID:  20976528] 
[24] 
Van Goor F, Straley KS, Cao D, et al. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol  2006; 290(6): L1117-30.
[http://dx.doi.org/10.1152/ajplung.00169.2005] [PMID:  16443646] 
[25] 
Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA  2011; 108(46): 18843-8.
[http://dx.doi.org/10.1073/pnas.1105787108] [PMID:  21976485] 
[26] 
Giuliano KA, Wachi S, Drew L, et al. Use of a high-throughput phenotypic screening strategy to identify amplifiers, a novel pharmacological class of small molecules that exhibit functional synergy with potentiators and correctors. SLAS Discov  2018; 23(2): 111-21.
[http://dx.doi.org/10.1177/2472555217729790] [PMID:  28898585] 
[27] 
Chung WJ, Goeckeler-Fried JL, Havasi V, et al. Increasing the endoplasmic reticulum pool of the f508del allele of the cystic fibrosis transmembrane conductance regulator leads to greater folding correction by small molecule therapeutics. PLoS One  2016; 11(10)e0163615
[http://dx.doi.org/10.1371/journal.pone.0163615] [PMID:  27732613] 
[28] 
Mutyam V, Du M, Xue X, et al. Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. Am J Respir Crit Care Med  2016; 194(9): 1092-103.
[http://dx.doi.org/10.1164/rccm.201601-0154OC] [PMID:  27104944] 
[29] 
Hinzpeter A, Aissat A, de Becdelièvre A, et al. Alternative splicing of in-frame exon associated with premature termination codons: implications for readthrough therapies. Hum Mutat  2013; 34(2): 287-91.
[http://dx.doi.org/10.1002/humu.22236] [PMID:  23065710] 
[30] 
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med  2011; 365(18): 1663-72.
[http://dx.doi.org/10.1056/NEJMoa1105185] [PMID:  22047557] 
[31] 
De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros  2014; 13(6): 674-80.
[http://dx.doi.org/10.1016/j.jcf.2014.09.005] [PMID:  25266159] 
[32] 
Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med  2016; 4(2): 107-15.
[http://dx.doi.org/10.1016/S2213-2600(15)00545-7] [PMID:  26803277] 
[33] 
Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): A phase 3 single-arm study. Lancet Respir Med  2018; 6(7): 545-53.
[http://dx.doi.org/10.1016/S2213-2600(18)30202-9] [PMID:  29886024] 
[34] 
Guimbellot J, Solomon GM, Baines A, et al. Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations. J Cyst Fibros  2018; 18(1): 102-9.
[http://dx.doi.org/10.1016/j.jcf.2018.04.004] [PMID:  29685811] 
[35] 
https://www.cff.org/News/News-Archive/2017/
[36] 
Hayes D Jr, McCoy KS, Sheikh SI. Improvement of sinus disease in cystic fibrosis with ivacaftor therapy. Am J Respir Crit Care Med  2014; 190(4): 468.
[http://dx.doi.org/10.1164/rccm.201403-0595IM] [PMID:  25127305] 
[37] 
Hayes D Jr, McCoy KS, Sheikh SI. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Respir Crit Care Med  2014; 190(5): 590-1.
[http://dx.doi.org/10.1164/rccm.201405-0882LE] [PMID:  25171312] 
[38] 
Kounis I, Lévy P, Rebours V. Ivacaftor CFTR potentiator therapy is efficient for pancreatic manifestations in cystic fibrosis. Am J Gastroenterol  2018; 113(7): 1058-9.
[http://dx.doi.org/10.1038/s41395-018-0123-7] [PMID:  29887601] 
[39] 
Cystic fibrosis foundation patient registry 2016 Annual Data
Report. Bethesda, MD. 2017.
[40] 
The Clinical and Functional TRanslation of CFTR (CFTR2). http://cftr2.org
[41] 
Jackson AD, Goss CH. Epidemiology of CF: How registries can be used to advance our understanding of the CF population. J Cyst Fibros  2018; 17(3): 297-305.
[http://dx.doi.org/10.1016/j.jcf.2017.11.013] [PMID:  29275954] 
[42] 
Boyle MP, Bell SC, Konstan MW, et al. VX09-809-102 study group. 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  2014; 2(7): 527-38.
[http://dx.doi.org/10.1016/S2213-2600(14)70132-8] [PMID:  24973281] 
[43] 
Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med  2015; 373(18): 1783-4.
[http://dx.doi.org/10.1056/NEJMc1510466] [PMID:  26510034] 
[44] 
Ren CL, Morgan RL, Oermann C. Cystic fibrosis foundation pulmonary guidelines: Use of CFTR modulator therapy in patients with cystic fibrosis. Ann Am Thorac Soc  2018; 15(3): 271-80.
[http://dx.doi.org/10.1513/AnnalsATS.201707-539OT] [PMID:  29342367] 
[45] 
Bulloch MN, Hanna C, Giovane R. Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation. Expert Rev Clin Pharmacol  2017; 10(10): 1055-72.
[http://dx.doi.org/10.1080/17512433.2017.1378094] [PMID:  28891346] 
[46] 
Ratjen F, Hug C, Marigowda G, et al. VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med  2017; 5(7): 557-67.
[http://dx.doi.org/10.1016/S2213-2600(17)30215-1] [PMID:  28606620] 
[47] 
Konstan MW, McKone EF, Moss RB, et al. 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 3, extension study. Lancet Respir Med  2017; 5(2): 107-18.
[http://dx.doi.org/10.1016/S2213-2600(16)30427-1] [PMID:  28011037] 
[48] 
Southern KW, Patel S, Sinha IP, Nevitt SJ. Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis. Cochrane Database Syst Rev 2018. 8CD010966
[http://dx.doi.org/10.1002/14651858.CD010966.pub2] [PMID:  30070364] 
[49] 
Talamo Guevara M, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf  2017; 16(11): 1305-11.
[http://dx.doi.org/10.1080/14740338.2017.1372419] [PMID:  28846049] 
[50] 
Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. N Engl J Med  2017; 377(21): 2013-23.
[http://dx.doi.org/10.1056/NEJMoa1709846] [PMID:  29099344] 
[51] 
Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med  2017; 377(21): 2024-35.
[http://dx.doi.org/10.1056/NEJMoa1709847] [PMID:  29099333] 
[52] 
Grootenhuis P, Van Goor F, Hadida S, et al. Discovery and biological profile of next-generation cftr correctors. Pediatr Pulmonol  2016; 51: 263.
[53] 
Pranke I, Bidou L, Martin N, et al. Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons. ERJ Open Res  2018; 4(1): 00080-2017.
[http://dx.doi.org/10.1183/23120541.00080-2017] [PMID:  29497617] 
[54] 
Wilschanski M, Miller LL, Shoseyov D, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J  2011; 38(1): 59-69.
[http://dx.doi.org/10.1183/09031936.00120910] [PMID:  21233271] 
[55] 
Kerem E, Konstan MW, De Boeck K, et al. Cystic Fibrosis Ataluren Study Group. Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med  2014; 2(7): 539-47.
[http://dx.doi.org/10.1016/S2213-2600(14)70100-6] [PMID:  24836205] 
[56] 
Zainal Abidin N, Haq IJ, Gardner AI, Brodlie M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin Pharmacother  2017; 18(13): 1363-71.
[http://dx.doi.org/10.1080/14656566.2017.1359255] [PMID:  28730885] 
[57] 
Miller JP, Drew L, Green O, et al. Cftr amplifiers: A new class of cftr modulator that complements the substrate limitations of other cf therapeutic modalities. Am J Respir Crit Care Med  2016; 193.
[58] 
Miller JP, Drew L, Green O, et al. Amplifiers are a new class of cftr modulators that increase the abundance of cftr protein and combined with potentiators and correctors enhance cftr chloride transport activity. Pediatr Pulmonol  2015; 50: S77-S107.
[59] 
Fajac I, De Boeck K. New horizons for cystic fibrosis treatment. Pharmacol Ther  2017; 170: 205-11.
[http://dx.doi.org/10.1016/j.pharmthera.2016.11.009] [PMID:  27916649] 
[60] 
Farinha CM, Matos P, Amaral MD. Control of cystic fibrosis transmembrane conductance regulator membrane trafficking: not just from the endoplasmic reticulum to the Golgi. FEBS J  2013; 280(18): 4396-406.
[http://dx.doi.org/10.1111/febs.12392] [PMID:  23773658] 
[61] 
Cheng SH, Gregory RJ, Marshall J, et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell  1990; 63(4): 827-34.
[http://dx.doi.org/10.1016/0092-8674(90)90148-8] [PMID:  1699669] 
[62] 
Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell  1995; 83(1): 129-35.
[http://dx.doi.org/10.1016/0092-8674(95)90241-4] [PMID:  7553864] 
[63] 
Farinha CM, Canato S. From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking. Cell Mol Life Sci  2017; 74(1): 39-55.
[http://dx.doi.org/10.1007/s00018-016-2387-7] [PMID:  27699454] 
[64] 
Amaral MD, Balch WE. Hallmarks of therapeutic management of the cystic fibrosis functional landscape. J Cyst Fibros  2015; 14(6): 687-99.
[http://dx.doi.org/10.1016/j.jcf.2015.09.006] [PMID:  26526359] 
[65] 
Hanrahan JW, Sampson HM, Thomas DY. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol Sci  2013; 34(2): 119-25.
[http://dx.doi.org/10.1016/j.tips.2012.11.006] [PMID:  23380248] 
[66] 
Esposito S, Tosco A, Villella VR, Raia V, Kroemer G, Maiuri L. Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis. Mol Cell Pediatr  2016; 3(1): 13.
[http://dx.doi.org/10.1186/s40348-016-0040-z] [PMID:  26976279] 
[67] 
Hutt DM, Loguercio S, Roth DM, Su AI, Balch WE. Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation. J Biol Chem  2018; 293(35): 13477-95.
[http://dx.doi.org/10.1074/jbc.RA118.003192] [PMID:  30006345] 
[68] 
Okiyoneda T, Veit G, Sakai R, et al. Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase. Dev Cell  2018; 44(6): 694-708.e7.
[http://dx.doi.org/10.1016/j.devcel.2018.02.001] [PMID:  29503157] 
[69] 
Angles F, Hutt DM, Balch WE. HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants. Hum Mol Genet  2019; 28(12): 1982-2000.
[http://dx.doi.org/10.1093/hmg/ddz026] 
[70] 
Hutt DM, Herman D, Rodrigues AP, et al. Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol  2010; 6(1): 25-33.
[http://dx.doi.org/10.1038/nchembio.275] [PMID:  19966789] 
[71] 
Luciani A, Villella VR, Esposito S, et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol  2010; 12(9): 863-75.
[http://dx.doi.org/10.1038/ncb2090] [PMID:  20711182] 
[72] 
Luciani A, Villella VR, Esposito S, et al. Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ΔF508 cystic fibrosis transmembrane conductance regulator. Autophagy  2012; 8(11): 1657-72.
[http://dx.doi.org/10.4161/auto.21483] [PMID:  22874563] 
[73] 
Farinha CM, Swiatecka-Urban A, Brautigan DL, Jordan P. Regulatory crosstalk by protein kinases on CFTR trafficking and activity. Front Chem  2016; 4: 1.
[http://dx.doi.org/10.3389/fchem.2016.00001] [PMID:  26835446] 
[74] 
Villella VR, Esposito S, Bruscia EM, et al. Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator. Cell Death Differ  2013; 20(8): 1101-15.
[http://dx.doi.org/10.1038/cdd.2013.46] [PMID:  23686137] 
[75] 
Maiuri L, Luciani A, Giardino I, et al. Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation. J Immunol  2008; 180(11): 7697-705.
[http://dx.doi.org/10.4049/jimmunol.180.11.7697] [PMID:  18490773] 
[76] 
Luciani A, Villella VR, Vasaturo A, et al. SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation. J Immunol  2009; 183(4): 2775-84.
[http://dx.doi.org/10.4049/jimmunol.0900993] [PMID:  19625650] 
[77] 
Ferrari E, Monzani R, Villella VR, et al. Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation. Cell Death Dis  2017; 8(1) e2544
[http://dx.doi.org/10.1038/cddis.2016.476] [PMID:  28079883] 
[78] 
Romani L, Oikonomou V, Moretti S, et al. Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med  2017; 23(5): 590-600.
[http://dx.doi.org/10.1038/nm.4305] [PMID:  28394330] 
[79] 
Cozza G, Pinna LA, Moro S. Kinase CK2 inhibition: An update. Curr Med Chem  2013; 20(5): 671-93.
[http://dx.doi.org/10.2174/092986713804999312] [PMID:  23210774] 
[80] 
Luz S, Kongsuphol P, Mendes AI, et al. Contribution of casein kinase 2 and spleen tyrosine kinase to CFTR trafficking and protein kinase A-induced activity. Mol Cell Biol  2011; 31(22): 4392-404.
[http://dx.doi.org/10.1128/MCB.05517-11] [PMID:  21930781] 
[81] 
Pagano MA, Marin O, Cozza G, et al. Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2. Biochem J  2010; 426(1): 19-29.
[http://dx.doi.org/10.1042/BJ20090813] [PMID:  19925455] 
[82] 
Venerando A, Franchin C, Cant N, et al. Detection of phospho-sites generated by protein kinase CK2 in CFTR: Mechanistic aspects of Thr1471 phosphorylation. PLoS One  2013; 8(9) e74232
[http://dx.doi.org/10.1371/journal.pone.0074232] [PMID:  24058532] 
[83] 
Venerando A, Ruzzene M, Pinna LA. Casein kinase: The triple meaning of a misnomer. Biochem J  2014; 460(2): 141-56.
[http://dx.doi.org/10.1042/BJ20140178] [PMID:  24825444] 
[84] 
De Stefano D, Villella VR, Esposito S, et al. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy  2014; 10(11): 2053-74.
[http://dx.doi.org/10.4161/15548627.2014.973737] [PMID:  25350163] 
[85] 
Tosco A, De Gregorio F, Esposito S, et al. A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Cell Death Differ  2016; 23(8): 1380-93.
[http://dx.doi.org/10.1038/cdd.2016.22] [PMID:  27035618] 
[86] 
Griesenbach U, Geddes DM, Alton EW. Gene therapy for cystic fibrosis: an example for lung gene therapy. Gene Ther  2004; 11(Suppl. 1): S43-50.
[http://dx.doi.org/10.1038/sj.gt.3302368] [PMID:  15454956] 
[87] 
Marangi M, Pistritto G. Innovative therapeutic strategies for cystic fibrosis: Moving forward to CRISPR technique. Front Pharmacol  2018; 9: 396.
[http://dx.doi.org/10.3389/fphar.2018.00396] [PMID:  29731717] 
[88] 
Alton EW, Boyd AC, Davies JC, et al. Genetic medicines for CF: Hype versus reality. Pediatr Pulmonol  2016; 51(S44): S5-S17.
[http://dx.doi.org/10.1002/ppul.23543] [PMID:  27662105] 
[89] 
Carlon MS, Vidović D, Birket S. Roadmap for an early gene therapy for cystic fibrosis airway disease. Prenat Diagn  2017; 37(12): 1181-90.
[http://dx.doi.org/10.1002/pd.5164] [PMID:  28981983] 
[90] 
Villate-Beitia I, Zarate J, Puras G, Pedraz JL. Gene delivery to the lungs: pulmonary gene therapy for cystic fibrosis. Drug Dev Ind Pharm  2017; 43(7): 1071-81.
[http://dx.doi.org/10.1080/03639045.2017.1298122] [PMID:  28270008] 
[91] 
Mitomo K, Griesenbach U, Inoue M, et al. Toward gene therapy for cystic fibrosis using a lentivirus pseudotyped with Sendai virus envelopes. Mol Ther  2010; 18(6): 1173-82.
[http://dx.doi.org/10.1038/mt.2010.13] [PMID:  20332767] 
[92] 
Martini SV, Rocco PR, Morales MM. Adeno-associated virus for cystic fibrosis gene therapy. Braz J Med Biol Res  2011; 44(11): 1097-104.
[http://dx.doi.org/10.1590/S0100-879X2011007500123] [PMID:  21952739] 
[93] 
Hart SL, Harrison PT. Genetic therapies for cystic fibrosis lung disease. Curr Opin Pharmacol  2017; 34: 119-24.
[http://dx.doi.org/10.1016/j.coph.2017.10.006] [PMID:  29107808] 
[94] 
van Haasteren J, Hyde SC, Gill DR. Lessons learned from lung and liver in-vivo gene therapy: Implications for the future. Expert Opin Biol Ther  2018; 18(9): 959-72.
[http://dx.doi.org/10.1080/14712598.2018.1506761] [PMID:  30067117] 
[95] 
Alton EWFW, Armstrong DK, Ashby D, et al. UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: A randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med  2015; 3(9): 684-91.
[http://dx.doi.org/10.1016/S2213-2600(15)00245-3] [PMID:  26149841] 
[96] 
Alton EW, Beekman JM, Boyd AC, et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax  2017; 72(2): 137-47.
[http://dx.doi.org/10.1136/thoraxjnl-2016-208406] [PMID:  27852956] 
[97] 
Robinson E, MacDonald KD, Slaughter K, et al. Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Mol Ther  2018; 26(8): 2034-46.
[http://dx.doi.org/10.1016/j.ymthe.2018.05.014] [PMID:  29910178] 
[98] 
White MK, Kaminski R, Young WB, Roehm PC, Khalili K. CRISPR editing technology in biological and biomedical investigation. J Cell Biochem  2017; 118(11): 3586-94.
[http://dx.doi.org/10.1002/jcb.26099] [PMID:  28460414] 
[99] 
Jusiak B, Cleto S, Perez-Piñera P, Lu TK. Engineering synthetic gene circuits in living cells with CRISPR technology. Trends Biotechnol  2016; 34(7): 535-47.
[http://dx.doi.org/10.1016/j.tibtech.2015.12.014] [PMID:  26809780] 
[100] 
Casini A, Olivieri M, Petris G, et al. A highly specific SpCas9 variant is identified by in vivo screening in yeast. Nat Biotechnol  2018; 36(3): 265-71.
[http://dx.doi.org/10.1038/nbt.4066] [PMID:  29431739] 
[101] 
Begemann MB, Gray BN, January E, et al. Precise insertion and guided editing of higher plant genomes using Cpf1 CRISPR nucleases. Sci Rep  2017; 7(1): 11606.
[http://dx.doi.org/10.1038/s41598-017-11760-6] [PMID:  28912524] 
[102] 
Ruge CA, Kirch J, Lehr CM. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers-therapeutic possibilities and technological challenges. Lancet Respir Med  2013; 1(5): 402-13.
[http://dx.doi.org/10.1016/S2213-2600(13)70072-9] [PMID:  24429205] 
[103] 
Shchors K, Massaras A, Hanahan D. Dual Targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal autophagy and therapeutic benefit. Cancer Cell  2015; 28(4): 456-71.
[http://dx.doi.org/10.1016/j.ccell.2015.08.012] [PMID:  26412325] 
[104] 
Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol  2016; 8: 127-40.
[http://dx.doi.org/10.2147/CPAA.S100759] [PMID:  27703398] 
[105] 
Dey I, Shah K, Bradbury NA. Natural compounds as therapeutic agents in the treatment cystic fibrosis. J Genet Syndr Gene Ther  2016; 7(1): 7.
[http://dx.doi.org/10.4172/2157-7412.1000284] [PMID:  27081574] 
[106] 
Leier G, Bangel-Ruland N, Sobczak K, Knieper Y, Weber WM. Sildenafil acts as potentiator and corrector of CFTR but might be not suitable for the treatment of CF lung disease. Cell Physiol Biochem  2012; 29(5-6): 775-90.
[http://dx.doi.org/10.1159/000265129] [PMID:  22613978] 
[107] 
Taylor-Cousar JL, Wiley C, Felton LA, et al. Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease. J Cyst Fibros  2015; 14(2): 228-36.
[http://dx.doi.org/10.1016/j.jcf.2014.10.006] [PMID:  25466700] 
[108] 
Lubamba B, Lecourt H, Lebacq J, et al. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med 2008;177:506-15Balfour-Lynn IM. Personalised medicine in cystic fibrosis is unaffordable. Paediatr Respir Rev  2014; 15(S1): 2-5.
[109] 
Carlile GW, Robert R, Goepp J, et al. Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking. J Cyst Fibros  2015; 14(1): 16-25.
[http://dx.doi.org/10.1016/j.jcf.2014.06.001] [PMID:  24974227] 
[110] 
Leonard A, Lebecque P, Dingemanse J, Leal T. A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference. J Cyst Fibros  2012; 11(3): 231-6.
[http://dx.doi.org/10.1016/j.jcf.2011.12.004] [PMID:  22281182] 
[111] 
Woodworth BA. Resveratrol ameliorates abnormalities of fluid and electrolyte secretion in a hypoxia-Induced model of acquired CFTR deficiency. Laryngoscope  2015; 125(S7)(Suppl. 7): S1-S13.
[http://dx.doi.org/10.1002/lary.25335] [PMID:  25946147] 
[112] 
Zhang Y, Yu B, Sui Y, Gao X, Yang H, Ma T. Identification of resveratrol oligomers as inhibitors of cystic fibrosis transmembrane conductance regulator by high-throughput screening of natural products from chinese medicinal plants. PLoS One  2014; 9(4) e94302
[http://dx.doi.org/10.1371/journal.pone.0094302] [PMID:  24714160] 
[113] 
Zhang S, Blount AC, McNicholas CM, et al. Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability. PLoS One  2013; 8(11) e81589
[http://dx.doi.org/10.1371/journal.pone.0081589] [PMID:  24282612] 
[114] 
Dhooghe B, Bouckaert C, Capron A, Wallemacq P, Leal T, Noel S. Resveratrol increases F508del-CFTR dependent salivary secretion in cystic fibrosis mice. Biol Open  2015; 4(7): 929-36.
[http://dx.doi.org/10.1242/bio.010967] [PMID:  26092868] 
[115] 
Mutyam V, Du M, Xue X. Discovery of clinically approved agents that promote suppression of CFTR nonsense mutations. Am J Respir Crit Care Med  2016; 194: 1092-103.
[http://dx.doi.org/10.1164/rccm.201601-0154OC] [PMID:  27104944] 
[116] 
Sun W, Sanderson PE, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today  2016; 21(7): 1189-95.
[http://dx.doi.org/10.1016/j.drudis.2016.05.015] [PMID:  27240777] 
[117] 
Elborn JS. Personalised medicine for cystic fibrosis: Treating the basic defect. Eur Respir Rev  2013; 22(127): 3-5.
[http://dx.doi.org/10.1183/09059180.00008112] [PMID:  23457158] 
[118] 
Schork NJ. Personalized medicine: Time for one-person trials. Nature  2015; 520(7549): 609-11.
[http://dx.doi.org/10.1038/520609a] [PMID:  25925459] 
[119] 
De Boeck K, Kent L, Davies J, et al. European cystic fibrosis society clinical trial network standardisation committee. CFTR biomarkers: Time for promotion to surrogate end-point. Eur Respir J  2013; 41(1): 203-16.
[http://dx.doi.org/10.1183/09031936.00057512] [PMID:  22878883] 
[120] 
Dekkers JF, Wiegerinck CL, de Jonge HR, et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med  2013; 19(7): 939-45.
[http://dx.doi.org/10.1038/nm.3201] [PMID:  23727931] 
[121] 
Dekkers JF, Gogorza Gondra RA, Kruisselbrink E, et al. Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids. Eur Respir J  2016; 48(2): 451-8.
[http://dx.doi.org/10.1183/13993003.01192-2015] [PMID:  27103391] 
[122] 
Di Lullo AM, Scorza M, Amato F, et al. An “ex vivo model” contributing to the diagnosis and evaluation of new drugs in cystic fibrosis. Acta Otorhinolaryngol Ital  2017; 37: 207-13.
Cite As
Current Respiratory Medicine Reviews

Cystic Fibrosis: New Insights into Therapeutic Approaches

Abstract

Graphical Abstract
