Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors

Pediatric Pulmonology

Volumn 50, Issue , 2015, Pages S3-S13

  Solomon, George M ^a   Marshall, Susan G ^b   Ramsey, Bonnie W ^b,c   Rowe, Steven M ^a,d  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^b UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^c SEATTLE CHILDREN S RESEARCH INSTITUTE   (United States)

^d UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

Author keywords

CFTR modulators; CFTR molecular defect; cystic fibrosis; lung disease; novel therapies

Indexed keywords

1 (2,2 DIFLUORO 1,3 BENZODIOXOL 5 YL) N [1 (2,3 DIHYDROXYPROPYL) 6 FLUORO 2 (2 HYDROXY 1,1 DIMETHYLETHYL) 1H INDOL 5 YL]CYCLOPROPANECARBOXAMIDE; BICARBONATE; CHLORIDE ION; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; HISTONE DEACETYLASE INHIBITOR; IVACAFTOR; LUMACAFTOR; NITRIC OXIDE; PLACEBO; RIOCIGUAT; VARDENAFIL; 1,3 BENZODIOXOLE DERIVATIVE; AMINOPHENOL DERIVATIVE; AMINOPYRIDINE DERIVATIVE; CFTR PROTEIN, HUMAN; QUINOLONE DERIVATIVE;

AMINO ACID SUBSTITUTION; BODY MASS; CHANNEL GATING; CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION; CYSTIC FIBROSIS; DISEASE EXACERBATION; DRUG MEGADOSE; DRUG SCREENING; ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION; FORCED EXPIRATORY VOLUME; FORCED VITAL CAPACITY; GENE MUTATION; HIGH THROUGHPUT SCREENING; HOMOZYGOTE; HUMAN; ION TRANSPORT; MONOTHERAPY; NONHUMAN; PRIORITY JOURNAL; PSEUDOMONAS AERUGINOSA; PULMONARY HYPERTENSION; QUALITY OF LIFE; REVIEW; SPUTUM CULTURE; ANIMAL; CLINICAL TRIAL (TOPIC); DRUG DESIGN; GENETICS; MOLECULARLY TARGETED THERAPY; MOUSE; MUTATION; PROTEIN FOLDING;

AMINOPHENOLS; AMINOPYRIDINES; ANIMALS; BENZODIOXOLES; CLINICAL TRIALS AS TOPIC; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; DRUG DESIGN; HOMOZYGOTE; HUMANS; MICE; MOLECULAR TARGETED THERAPY; MUTATION; PROTEIN FOLDING; QUINOLONES;

EID: 84941166975     PISSN: 87556863     EISSN: 10990496     Source Type: Journal    
DOI: 10.1002/ppul.23240     Document Type: Review

References (85)

1. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC., Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073-1080.
2. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al., Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066-1073.
3. Berger HA, Anderson MP, Gregory RJ, Thompson S, Howard PW, Maurer RA, Mulligan R, Smith AE, Welsh MJ., Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel. J Clin Invest 1991; 88: 1422-1431.
4. Gadsby DC, Vergani P, Csanady L., The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006; 440: 477-483.
5. Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, Boucher RC., Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998; 95: 1005-1015.
6. Birket SE, Chu KK, Liu L, Houser GH, Diephuis BJ, Wilsterman EJ, Dierksen G, Mazur M, Shastry S, Li Y, Watson JD, Smith AT, Schuster BS, Hanes J, Grizzle WE, Sorscher EJ, Tearney GJ, Rowe SM., A functional anatomic defect of the cystic fibrosis airway. Am J Respir Crit Care Med 2014; 190: 421-432.
7. Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, Awadalla MA, Moninger TO, Michalski AS, Hoffman EA, Zabner J, Stoltz DA, Welsh MJ., Cystic fibrosis. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 2014; 345: 818-822.
8. Stoltz DA, Meyerholz DK, Welsh MJ., Origins of cystic fibrosis lung disease. N Engl J Med 2015; 372: 351-362.
9. Gibson RL, Burns JL, Ramsey BW., Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918-951.
10. Rowe SM, Miller S, Sorscher EJ., Cystic fibrosis. N Engl J Med 2005; 352: 1992-2001.
11. Linsdell P., Functional architecture of the CFTR chloride channel. Mol Membr Biol 2014; 31: 1-16.
12. Riordan JR., CFTR function and prospects for therapy. Annu Rev Biochem 2008; 77: 701-726.
13. Ward CL, Omura S, Kopito RR., Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 1995; 83: 121-127.
14. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P., Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 2009; 106: 18825-18830.
15. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR., Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013; 45: 1160-1167.
16. Okiyoneda T, Lukacs GL., Fixing cystic fibrosis by correcting CFTR domain assembly. J Cell Biol 2012; 199: 199-204.
17. Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ., Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 1992; 358: 761-764.
18. Bernier V, Lagace M, Bichet DG, Bouvier M., Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 2004; 15: 222-228.
19. Rubenstein RC, Egan ME, Zeitlin PL., In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest 1997; 100: 2457-2465.
20. Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glockner-Pagel J, Canny S, Du K, Lukacs GL, Caplan MJ., Curcumin a major constituent of turmeric, corrects cystic fibrosis defects. Science 2004; 304: 600-602.
21. McCarty NA, Standaert TA, Teresi M, Tuthill C, Launspach J, Kelley TJ, Milgram LJ, Hilliard KA, Regelmann WE, Weatherly MR, Aitken ML, Konstan MW, Ahrens RC., A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis. Pediatr Pulmonol 2002; 33: 90-98.
22. Van Goor F, Straley KS, Cao D, Gonzalez J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PD, Negulescu P., 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: L1117-1130.
23. Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ, Verkman AS., Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest 2005; 115: 2564-2571.
24. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA., Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011; 108: 18843-18848.
25. Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M., Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; 372: 719-727.
26. Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL., Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 2010; 182: 1262-1272.
27. Griesenbach U, Geddes DM, Alton EW., Update on gene therapy for cystic fibrosis. Curr Opin Mol Ther 2003; 5: 489-494.
28. Prickett M, Jain M., Gene therapy in cystic fibrosis. Transl Res: J Lab Clin Med 2013; 161: 255-264.
29. Cystic Fibrosis Foundation Patient Registry 2013. http://wwwcfforg/UploadedFiles/research/ClinicalResearch/PatientRegistryReport/2013-CFF-Patient-Registry-Annual-Data-Reportpdf.
30. Clancy JP, Jain M., Personalized medicine in cystic fibrosis: dawning of a new era. Am J Respir Crit Care Med 2012; 186: 593-597.
31. Sloane PA, Rowe SM., Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. Curr Opin Pulm Med 2010; 16: 591-597.
32. Van Goor F, Yu H, Burton B, Hoffman BJ., Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014; 13: 29-36.
33. Vertex Press Release: Vertex Announces Upcoming Presentations of Data at North American Cystic Fibrosis Conference-October 9 to 11, 2014. http://investorsvrtxcom/releasedetailcfm?ReleaseID=869555 2014.
34. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ., Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 1993; 362: 160-164.
35. Bompadre SG, Sohma Y, Li M, Hwang TC., G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol 2007; 129: 285-298.
36. Sermet-Gaudelus I, de Blic J, LeBourgeois M, Pranke I, Edelman A, Ramsey BW., Potentiating and correcting mutant CFTR in patients with cystic fibrosis. In:, Mall MA, Elborn JS, editors. Cystic Fibrosis. Volume 64. Wakefield, UK: European Respiratory Society; 2014. pp 129-149.
37. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW., Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010; 363: 1991-2003.
38. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS, Group VXS., A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663-1672.
39. Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R, Group VXS., 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 2013; 187: 1219-1225.
40. McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright CE, Ratjen F, Sermet-Gaudelus I, Plant B, Jiang Y, Gilmartin G, Davies JC., Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the G551D-CFTR mutation: response through 144 weeks of treatment (96 weeks of PERSIST). Pediatr Pulmonol Suppl 2013; 48: 287.
41. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW, Network GIotCFFTD. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175-184.
42. Heltshe SL, Mayer-Hamblett N, Burns JL, Khan U, Baines A, Ramsey BW, Rowe SM, Network GIotCFFTD. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60: 703-712.
43. Zemanick ET, Harris JK, Wagner BD, Robertson CE, Sagel SD, Stevens MJ, Accurso FJ, Laguna TA., Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. PloS ONE 2013; 8: e62917.
44. Gelfond D, Ma C, Semler J, Borowitz D., Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 2013; 58: 2275-2281.
45. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M., Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014; 13:Published online September 26, 2014.
46. Vertex Press Release: Vertex Submits Supplemental New Drug Application (sNDA) to U.S. Food and Drug Administration for Use of KALYDECO® (ivacaftor) in People 18 and Older with Cystic Fibrosis who have the R117H Mutation. http://investorsvrtxcom/releasedetailcfm?ReleaseID=857163 2014.
47. Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, Geller DE, Group VXS., Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142: 718-724.
48. Yousef S, Solomon GM, Brody A, Rowe SM, Colin AA., Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation. Chest 2015; 147: e79-82.
49. Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ., Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences. Cell 2012; 148: 164-174.
50. Rabeh WM, Bossard F, Xu H, Okiyoneda T, Bagdany M, Mulvihill CM, Du K, di Bernardo S, Liu Y, Konermann L, Roldan A, Lukacs GL., Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function. Cell 2012; 148: 150-163.
51. Wang C, Protasevich I, Yang Z, Seehausen D, Skalak T, Zhao X, Atwell S, Spencer Emtage J, Wetmore DR, Brouillette CG, Hunt JF., Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis. Protein Sci 2010; 19: 1932-1947.
52. Aleksandrov AA, Kota P, Cui L, Jensen T, Alekseev AE, Reyes S, He L, Gentzsch M, Aleksandrov LA, Dokholyan NV, Riordan JR., Allosteric modulation balances thermodynamic stability and restores function of DeltaF508 CFTR. J Mol Biol 2012; 419: 41-60.
53. Lazrak A, Fu L, Bali V, Bartoszewski R, Rab A, Havasi V, Keiles S, Kappes J, Kumar R, Lefkowitz E, Sorscher EJ, Matalon S, Collawn JF, Bebok Z., FASEB J 2013; 27: 4630-4645.
54. Bartoszewski RA, Jablonsky M, Bartoszewska S, Stevenson L, Dai Q, Kappes J, Collawn JF, Bebok Z., A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein. J Biol Chem 2010; 285: 28741-28748.
55. Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV, Riordan JR., Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci USA 2008; 105: 3256-3261.
56. Jurkuvenaite A, Varga K, Nowotarski K, Kirk KL, Sorscher EJ, Li Y, Clancy JP, Bebok Z, Collawn JF., Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. J Biol Chem 2006; 281: 3329-3334.
57. Pedemonte N, Tomati V, Sondo E, Galietta LJ., Influence of cell background on pharmacological rescue of mutant CFTR. Am J Physiol: Cell Physiol 298: C866-874.
58. Rowe SM, Pyle LC, Jurkevante A, Varga K, Collawn J, Sloane PA, Woodworth B, Mazur M, Fulton J, Fan L, Li Y, Fortenberry J, Sorscher EJ, Clancy JP., DeltaF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers. Pulm Pharmacol Ther 2010; 23: 268-278.
59. Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL., Mechanism-based corrector combination restores DeltaF508-CFTR folding and function. Nat Chem Biol 2013; 9: 444-454.
60. Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordonez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW., 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 2012; 67: 12-18.
61. Marigowda G, Liu F, Waltz D., Effect of bronchodilators in health individiuals receiving lumacaftor in combination with ivacaftor peds pulmonary 2014; Supplment 38.
62. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D, on behalf of the VXSG. 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: 527-538.
63. Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP., Effect of 8 weeks of lumacaftor in combination with ivacaftor in patients with CF and heterozygous for the F508del CFTR mutation. Peds Pulm 2014;Supplement 38.
64. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP, Traffic Groups, TS., Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; [Epub ahead of print].
65. Rosenfeld M, Marigowda G, Liu F, Waltz D., Effect of lumacaftor in combination with ivacaftor on FEV1 and safety measures in patients aged 6-11 years with CF who are homozygous for F508del-CFTR. Peds Pulm 2014;Supplement 38.
66. Vertex Press Release: Two 24-Week Phase 3 Studies of Lumacaftor in Combination with Ivacaftor Met Primary Endpoint with Statistically Significant Improvements in Lung Function (FEV1) in People with Cystic Fibrosis who have Two Copies of the F508del Mutation. http://investorsvrtxcom/releasedetailcfm?ReleaseID=856185 2014.
67. Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE, Hegedus T, Verkman AS, Lukacs GL., Some gating potentiators, including VX-770, diminish DeltaF508-CFTR functional expression. Sci Transl Med 2014; 6:246ra 297.
68. Cholon DM, Quinney NL, Fulcher ML, Esther CR, Jr., Das J, Dokholyan NV, Randell SH, Boucher RC, Gentzsch M., Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis. Sci Transl Med 2014; 6:246ra 296.
69. Liu X, Dawson DC., Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators protect G551D but not DeltaF508 CFTR from thermal instability. Biochemistry 2014; 53: 5613-5618.
70. Donaldson SH, Pilewski JM, Cooke J, Himes-Lekstrom J., Addition of VX-661, an investigational CFTR corrector, to ivacaftor, a CFTR potentiator, in patients with CF and heterozygous for F508del/G551D-CFTR. Peds Pulm 2014;Supplement 38.
71. Vertex Press Release: Treatment with VX-661 and Ivacaftor in a Phase 2 Study Resulted in Statistically Significant Improvements in Lung Function in People with Cystic Fibrosis Who Have Two Copies of the F508del Mutation. http://investorsvrtxcom/releasedetailcfm?ReleaseID=757597 2013.
72. DeSouza SA, Preston IR., The safety and effectiveness of riociguat to treat chronic thromboembolic pulmonary hypertension. Expert Rev Cardiovasc Ther 2015; 13: 1-10.
73. Green LS, Chun LE, Patton AK, Sun X, Rosenthal GJ, Richards JP., Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase. Biochemistry 2012; 51: 2157-2168.
74. Blonder JP, Look K, Sun X, Sui J, Qiu J, Scoggin C, Gabriel SE., A novel GSNOR inhibitor with potent bronchodilator effects and CFTR potentiation activity. Peds Pulm 2013; Supplment 36.
75. Blonder JP, Quinney NL, Looker D, Sun X, Gentzsch M, Scoggin C, Gabriel SE., Intestinal current measurement to assess modulation of F508del-CFTR function by GSNOR inhibitor treatment in Vivo. Peds Pulm 2013; Supplement 36.
76. Donaldson SH, Taylor-Cousar JL, Rosenbluth DB, Zeitlin P, Chmiel J, Jain M, Mckoy KS, Zemanick ET., Safety, Tolerability, and Pharmacokinetics of the Intravenous S-Nitrosoglutathione Reductase Inhibitor N6022: an Ascending Dose Study in Subjects Homozygous for the F508Del-CFTR Mutation. Peds Pulm 2014; Supplement 38.
77. Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW., Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol 2008; 73: 478-489.
78. Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T., Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med 2008; 177: 506-515.
79. Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T,. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med 2008; 177: 506-515.
80. Dhooghe B, Noel S, Bouzin C, Behets-Wydemans G, Leal T., Correction of chloride transport and mislocalization of CFTR protein by vardenafil in the gastrointestinal tract of cystic fibrosis Mice. PloS ONE 2013; 8: e77314.
81. Kim Chiaw, P, Wellhauser L, Huan LJ, Ramjeesingh M, Bear C., A chemical corrector modifies the channel function of F508del-CFTR. Mol Pharmacol 78: 411-418.
82. Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR., III, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE., Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol 2010; 6: 25-33.
83. Mu TW, Ong DS, Wang YJ, Balch WE, Yates JR, III, Segatori L, Kelly JW., Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 2008; 134: 769-781.
84. Varga K, Goldstein RF, Jurkuvenaite A, Chen L, Matalon S, Sorscher EJ, Bebok Z, Collawn JF., Enhanced cell-surface stability of rescued DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) by pharmacological chaperones. Biochem J 2008; 410: 555-564.
85. Young A, Gentzsch M, Abban CY, Jia Y, Meneses PI, Bridges RJ, Bradbury NA., Dynasore inhibits removal of wild-type and DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) from the plasma membrane. Biochem J 2009; 421: 377-385.