1932

Abstract

Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disorder in the Caucasian population and occurs in many other ethnicities worldwide. The daily treatment burden is substantial for CF patients even when they are well, with numerous pharmacologic and physical therapies targeting lung disease requiring the greatest time commitment. CF treatments continue to advance with greater understanding of factors influencing long-term morbidity and mortality. In recent years, in-depth understanding of genetic and protein structure-function relationships has led to the introduction of targeted therapies for patients with specific CF genotypes. With these advances, CF has become a model of personalized or precision medicine. The near future will see greater access to targeted therapies for most patients carrying common mutations, which will mandate individualized bench-to-bedside methodologies for those with rare genotypes.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-090314-050024
2016-08-31
2024-06-22
Loading full text...

Full text loading...

/deliver/fulltext/genom/17/1/annurev-genom-090314-050024.html?itemId=/content/journals/10.1146/annurev-genom-090314-050024&mimeType=html&fmt=ahah

Literature Cited

  1. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM. 1.  et al. 2010. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N. Engl. J. Med. 363:1991–2003 [Google Scholar]
  2. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr. 2.  2011. Azithromycin for prevention of exacerbations of COPD. N. Engl. J. Med. 365:689–98 [Google Scholar]
  3. Alonso y de los Ruyzes de Fontecha J. 3.  1606. Diez Previlegios para Mugeres Preñadas Madrid: Alcalá de Henares [Google Scholar]
  4. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH. 4.  et al. 2013. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 309:1251–59 [Google Scholar]
  5. Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D. 5.  et al. (UK Cyst. Fibros. Gene Therapy Consort.) 2015. 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. 3:684–91 [Google Scholar]
  6. Ambort D, Johansson ME, Gustafsson JK, Nilsson HE, Ermund A. 6.  et al. 2012. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. PNAS 109:5645–50 [Google Scholar]
  7. Andersen D. 7.  1938. Cystic fibrosis of the pancreas and its relation to celiac disease. Am. J. Dis. Child. 56:344–99 [Google Scholar]
  8. Anderson MP, Gregory RJ, Thompson S, Souza DW, Paul S. 8.  et al. 1991. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science 253:202–5 [Google Scholar]
  9. Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP. 9.  et al. 2005. Guide to bone health and disease in cystic fibrosis. J. Clin. Endocrinol. Metab. 90:1888–96 [Google Scholar]
  10. Armstrong DK, Cunningham S, Davies JC, Alton EW. 10.  2014. Gene therapy in cystic fibrosis. Arch. Dis. Child. 99:465–68 [Google Scholar]
  11. Assael BM, Pressler T, Bilton D, Fayon M, Fischer R. 11.  et al. 2013. Inhaled aztreonam lysine versus inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J. Cyst. Fibros. 12:130–40 [Google Scholar]
  12. Awadalla M, Miyawaki S, Abou Alaiwa MH, Adam RJ, Bouzek DC. 12.  et al. 2014. Early airway structural changes in cystic fibrosis pigs as a determinant of particle distribution and deposition. Ann. Biomed. Eng. 42:915–27 [Google Scholar]
  13. Banner KH, De Jonge H, Elborn S, Growcott E, Gulbins E. 13.  et al. 2009. Highlights of a workshop to discuss targeting inflammation in cystic fibrosis. J. Cyst. Fibros. 8:1–8 [Google Scholar]
  14. Barza M, Ioannidis JP, Cappelleri JC, Lau J. 14.  1996. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 312:338–45 [Google Scholar]
  15. Bedwell DM, Kaenjak A, Benos DJ, Bebok Z, Bubien JK. 15.  et al. 1997. Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat. Med. 3:1280–84 [Google Scholar]
  16. Bellin MD, Laguna T, Leschyshyn J, Regelmann W, Dunitz J. 16.  et al. 2013. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr. Diabetes 14:417–21 [Google Scholar]
  17. Bonfield TL, Hodges CA, Cotton CU, Drumm ML. 17.  2012. Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection. J. Leukoc. Biol. 92:1111–22 [Google Scholar]
  18. Borowitz D, Baker RD, Stallings V. 18.  2002. Consensus report on nutrition for pediatric patients with cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 35:246–59 [Google Scholar]
  19. Borowitz D, Robinson KA, Rosenfeld M, Davis SD. 19.  et al. 2009. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J. Pediatr. 155:S73–93 [Google Scholar]
  20. Boucher RC. 20.  2007. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu. Rev. Med. 58:157–70 [Google Scholar]
  21. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM. 21.  et al. 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. 2:527–38 [Google Scholar]
  22. Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. 22.  2002. Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest 121:64–72 [Google Scholar]
  23. Busch R. 23.  1990. On the history of cystic fibrosis. Acta Univ. Carol. Med. 36:13–15 [Google Scholar]
  24. Caci E, Folli C, Zegarra-Moran O, Ma T, Springsteel MF. 24.  et al. 2003. CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds. Am. J. Physiol. Lung Cell. Mol. Physiol. 285:L180–88 [Google Scholar]
  25. Char JE, Wolfe MH, Cho HJ, Park IH, Jeong JH. 25.  et al. 2014. A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. PLOS ONE 9:e88564 [Google Scholar]
  26. Chen G, Korfhagen TR, Karp CL, Impey S, Xu Y. 26.  et al. 2014. Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity. Am. J. Respir. Crit. Care Med. 189:301–13 [Google Scholar]
  27. Chen G, Korfhagen TR, Xu Y, Kitzmiller J, Wert SE. 27.  et al. 2009. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. J. Clin. Investig. 119:2914–24 [Google Scholar]
  28. Cheng SH, Rich DP, Marshall J, Gregory RJ, Welsh MJ, Smith AE. 28.  1991. Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66:1027–36 [Google Scholar]
  29. Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J. 29.  et al. 2014. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci. Transl. Med. 6:246ra96 [Google Scholar]
  30. Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG. 30.  1993. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat. Genet. 3:151–56 [Google Scholar]
  31. Chu CS, Trapnell BC, Murtagh JJ Jr, Moss J, Dalemans W. 31.  et al. 1991. Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium. EMBO J. 10:1355–63 [Google Scholar]
  32. Clancy JP, Bebok Z, Ruiz F, King C, Jones J. 32.  et al. 2001. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 163:1683–92 [Google Scholar]
  33. Clancy JP, Konstan MW, Rowe SM, Accurso F, Zeitlin P, Moss R. 33.  2006. A phase II study of PTC 124 in CF patients harboring premature stop mutations. Pediatr. Pulmonol. 41:S29269 [Google Scholar]
  34. Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS. 34.  et al. 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 67:12–18 [Google Scholar]
  35. 35. Cyst. Fibros. Found., Johns Hopkins Univ., Hosp. Sick Child 2015. Clinical and functional translation of CFTR (CFTR2). Updated Aug. 13. http://cftr2.org [Google Scholar]
  36. 36. Cyst. Fibros. Found. Patient Regist 2013. 2012 annual data report. Rep., Cyst. Fibros. Found., Bethesda, MD [Google Scholar]
  37. 37. Cyst. Fibros. Found. Patient Regist 2014. 2013 annual data report. Rep., Cyst. Fibros. Found., Bethesda, MD [Google Scholar]
  38. Davies JC, Sheridan H, Bell N, Cunningham S, Davis SD. 38.  et al. 2013. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir. Med. 1:630–38 [Google Scholar]
  39. Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS. 39.  et al. 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. 187:1219–25 [Google Scholar]
  40. De Boeck K, Munck A, Walker S, Faro A, Hiatt P. 40.  et al. 2014. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J. Cyst. Fibros. 13:674–80 [Google Scholar]
  41. Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM. 41.  et al. 2013. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat. Med. 19:939–45 [Google Scholar]
  42. Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ. 42.  1992. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358:761–64 [Google Scholar]
  43. Denning GM, Ostedgaard LS, Welsh MJ. 43.  1992. Abnormal localization of cystic fibrosis transmembrane conductance regulator in primary cultures of cystic fibrosis airway epithelia. J. Cell Biol. 118:551–59 [Google Scholar]
  44. Diwakar A, Adam RJ, Michalski AS, Tamegnon MM, Fischer AJ. 44.  et al. 2015. Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis. Laryngoscope 125:2398–404 [Google Scholar]
  45. Dodge JA. 45.  1995. Male fertility in cystic fibrosis. Lancet 346:587–88 [Google Scholar]
  46. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. 46.  2006. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N. Engl. J. Med. 354:241–50 [Google Scholar]
  47. Donaldson SH, Boucher RC. 47.  2007. Sodium channels and cystic fibrosis. Chest 132:1631–36 [Google Scholar]
  48. Donaldson SH, Pilewski J, Griese M, Dong Q, Lee PS. 48.  (VX11-661-101 Study Group) 2013. VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF and homozygous for the F508Del-CFTR mutation: interim analysis. J. Cyst. Fibros. 12:Suppl. 1S14 (Abstr.) [Google Scholar]
  49. Dranchak PK, Di Pietro E, Snowden A, Oesch N, Braverman NE. 49.  et al. 2011. Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations. J. Cell Biochem. 112:1250–58 [Google Scholar]
  50. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP. 50.  et al. 2006. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N. Engl. J. Med. 354:229–40 [Google Scholar]
  51. Emerson J, Rosenfeld M, McNamara S, Ramsey BW, Gibson RL. 51.  2002. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr. Pulmonol. 34:91–100 [Google Scholar]
  52. Engelhardt JF, Yankaskas JR, Ernst SA, Yang Y, Marino CR. 52.  et al. 1992. Submucosal glands are the predominant site of CFTR expression in the human bronchus. Nat. Genet. 2:240–48 [Google Scholar]
  53. Engelhardt JF, Zepeda M, Cohn JA, Yankaskas JR, Wilson JM. 53.  1994. Expression of the cystic fibrosis gene in adult human lung. J. Clin. Investig. 93:737–49 [Google Scholar]
  54. 54. Eur. Cyst. Fibros. Soc. Patient Regist 2010. Annual data report 2010. Rep., Eur. Cyst. Fibros. Soc., Karup, Den. [Google Scholar]
  55. Flume PA, Liou TG, Borowitz DS, Li H, Yen K. 55.  et al. 2012. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 142:718–24 [Google Scholar]
  56. Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt RL. 56.  et al. 2009. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am. J. Respir. Crit. Care Med. 180:802–8 [Google Scholar]
  57. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ. 57.  et al. 2007. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am. J. Respir. Crit. Care Med. 176:957–69 [Google Scholar]
  58. Flume PA, Robinson KA, O'Sullivan BP, Finder JD, Vender RL. 58.  et al. 2009. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir. Care 54:522–37 [Google Scholar]
  59. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML. 59.  et al. (Pulmozyme Study Group). 1994. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N. Engl. J. Med. 331:637–42 [Google Scholar]
  60. Galietta LJ, Springsteel MF, Eda M, Niedzinski EJ, By K. 60.  et al. 2001. Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J. Biol. Chem. 276:19723–28 [Google Scholar]
  61. Garrod AE, Hurtley WH. 61.  1912. Congenital family steatorrhea. Q. J. Med. 6:242–58 [Google Scholar]
  62. Gulbins E. 62.  2010. Lipids control mucus production in cystic fibrosis. Nat. Med. 16:267–68 [Google Scholar]
  63. Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE. 63.  et al. 2012. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 209:1263–72 [Google Scholar]
  64. Hayes D Jr, McCoy KS, Sheikh SI. 64.  2014. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am. J. Respir. Crit. Care Med. 190:590–91 [Google Scholar]
  65. Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ. 65.  et al. 2014. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 345:818–22 [Google Scholar]
  66. 66. Hosp. Sick Child 2015. Cystic fibrosis mutation database. http://www.genet.sickkids.on.ca [Google Scholar]
  67. Hudson VM. 67.  2001. Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic. Biol. Med. 30:1440–61 [Google Scholar]
  68. Iannuzzi MC, Collins FS. 68.  1990. Reverse genetics and cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 2:309–16 [Google Scholar]
  69. Jennings MT, Boyle MP, Weaver D, Callahan KA, Dasenbrook EC. 69.  2014. Eradication strategy for persistent methicillin-resistant Staphylococcus aureus infection in individuals with cystic fibrosis—the PMEP trial: study protocol for a randomized controlled trial. Trials 15:223 [Google Scholar]
  70. Jurkuvenaite A, Chen L, Bartoszewski R, Goldstein R, Bebok Z. 70.  et al. 2010. Functional stability of rescued ΔF508 cystic fibrosis transmembrane conductance regulator in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 42:363–72 [Google Scholar]
  71. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK. 71.  et al. 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–80 [Google Scholar]
  72. Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D. 72.  et al. 2008. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 372:719–27 [Google Scholar]
  73. Kerem E, Konstan MW, De Boeck K, Accurso FJ, Sermet-Gaudelus I. 73.  et al. 2014. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir. Med. 2:539–47 [Google Scholar]
  74. Knowles MR, Hohneker KW, Zhou Z, Olsen JC, Noah TL. 74.  et al. 1995. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 333:823–31 [Google Scholar]
  75. Konstan MW, Berger M. 75.  1997. Current understanding of the inflammatory process in cystic fibrosis: onset and etiology. Pediatr. Pulmonol. 24:137–42; discussion 159–61 [Google Scholar]
  76. Konstan MW, Byard PJ, Hoppel CL, Davis PB. 76.  1995. Effect of high-dose ibuprofen in patients with cystic fibrosis. N. Engl. J. Med. 332:848–54 [Google Scholar]
  77. Konstan MW, Davis PB, Wagener JS, Hilliard KA, Stern RC. 77.  et al. 2004. Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum. Gene Ther. 15:1255–69 [Google Scholar]
  78. Konstan MW, Ratjen F. 78.  2012. Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J. Cyst. Fibros. 11:78–83 [Google Scholar]
  79. Kopeikin Z, Yuksek Z, Yang HY, Bompadre SG. 79.  2014. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J. Cyst. Fibros. 13:508–14 [Google Scholar]
  80. Kovesi TA, Swartz R, MacDonald N. 80.  1998. Transient renal failure due to simultaneous ibuprofen and aminoglycoside therapy in children with cystic fibrosis. N. Engl. J. Med. 338:65–66 [Google Scholar]
  81. Lai HJ, Cheng Y, Farrell PM. 81.  2005. The survival advantage of patients with cystic fibrosis diagnosed through neonatal screening: evidence from the United States Cystic Fibrosis Foundation registry data. J. Pediatr. 147:Suppl.S57–63 [Google Scholar]
  82. Lam W, Tjon J, Seto W, Dekker A, Wong C. 82.  et al. 2007. Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients. J. Antimicrob. Chemother. 59:1135–40 [Google Scholar]
  83. Lands LC, Milner R, Cantin AM, Manson D, Corey M. 83.  2007. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J. Pediatr. 151:249–54 [Google Scholar]
  84. Lazarowski ER, Tarran R, Grubb BR, van Heusden CA, Okada S, Boucher RC. 84.  2004. Nucleotide release provides a mechanism for airway surface liquid homeostasis. J. Biol. Chem. 279:36855–64 [Google Scholar]
  85. Lebecque P, Leonard A, De Boeck K, De Baets F, Malfroot A. 85.  et al. 2009. Early referral to cystic fibrosis specialist centre impacts on respiratory outcome. J. Cyst. Fibros. 8:26–30 [Google Scholar]
  86. Linsdell P, Tabcharani JA, Hanrahan JW. 86.  1997. Multi-ion mechanism for ion permeation and block in the cystic fibrosis transmembrane conductance regulator chloride channel. J. Gen. Physiol. 110:365–77 [Google Scholar]
  87. Lorentzen D, Durairaj L, Pezzulo AA, Nakano Y, Launspach J. 87.  et al. 2011. Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions. Free Radic. Biol. Med. 50:1144–50 [Google Scholar]
  88. Lukacs GL, Chang XB, Bear C, Kartner N, Mohamed A. 88.  et al. 1993. The ΔF508 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. 268:21592–98 [Google Scholar]
  89. Malik V, Rodino-Klapac LR, Viollet L, Mendell JR. 89.  2010. Aminoglycoside-induced mutation suppression (stop codon readthrough) as a therapeutic strategy for Duchenne muscular dystrophy. Ther. Adv. Neurol. Disord. 3:379–89 [Google Scholar]
  90. Malik V, Rodino-Klapac LR, Viollet L, Wall C, King W. 90.  et al. 2010. Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann. Neurol. 67:771–80 [Google Scholar]
  91. Mall MA, Sheppard DN. 91.  2014. Chronic ivacaftor treatment: getting F508del-CFTR into more trouble?. J. Cyst. Fibros. 13:605–7 [Google Scholar]
  92. Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT. 92.  et al. 1998. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95:1005–15 [Google Scholar]
  93. Matsui H, Randell SH, Peretti SW, Davis CW, Boucher RC. 93.  1998. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J. Clin. Investig. 102:1125–31 [Google Scholar]
  94. Mayer-Hamblett N, Rosenfeld M, Treggiari MM, Konstan MW, Retsch-Bogart G. 94.  et al. 2013. Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis. Pediatr. Pulmonol. 48:943–53 [Google Scholar]
  95. McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW. 95.  et al. 2014. 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). Lancet Respir. Med. 2:902–10 [Google Scholar]
  96. Mendell JR, Rodino-Klapac LR, Malik V. 96.  2010. Molecular therapeutic strategies targeting Duchenne muscular dystrophy. J. Child Neurol. 25:1145–48 [Google Scholar]
  97. Mogayzel PJ, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D. 97.  et al. 2013. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am. J. Respir. Crit. Care Med. 187:680–89 [Google Scholar]
  98. Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJ. 98.  2013. Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. PNAS 110:18285–90 [Google Scholar]
  99. Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB. 99.  et al. 2007. A novel host defense system of airways is defective in cystic fibrosis. Am. J. Respir. Crit. Care Med. 175:174–83 [Google Scholar]
  100. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM. 100.  et al. 2015. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir. Med. 3:524–33 [Google Scholar]
  101. Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL. 101.  et al. 2007. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum. Gene Ther. 18:726–32 [Google Scholar]
  102. Obama B. 102.  2015. Remarks by the President in State of the Union Address Jan. 20. http://www.whitehouse.gov/the-press-office/2015/01/20/remarks-president-state-union-address-january-20-2015 [Google Scholar]
  103. Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O. 103.  et al. 2005. Small-molecule correctors of defective ΔF508-CFTR cellular processing identified by high-throughput screening. J. Clin. Investig. 115:2564–71 [Google Scholar]
  104. Peltz SW, Welch EM, Jacobson A, Trotta CR, Naryshkin N. 104.  et al. 2009. Nonsense suppression activity of PTC124 (ataluren). PNAS 106:E64; author reply E65 [Google Scholar]
  105. Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S. 105.  et al. 2012. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 487:109–13 [Google Scholar]
  106. Pohl K, Hayes E, Keenan J, Henry M, Meleady P. 106.  et al. 2014. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood 124:999–1009 [Google Scholar]
  107. Quan JM, Tiddens HAWM, Sy JP, McKenzie SG, Montgomery MD. 107.  et al. 2001. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J. Pediatr. 139:813–20 [Google Scholar]
  108. Que C, Cullinan P, Geddes D. 108.  2006. Improving rate of decline of FEV1 in young adults with cystic fibrosis. Thorax 61:155–57 [Google Scholar]
  109. Ramsey BW, Davies JC, McElvaney NG, Tullis E, Bell SC. 109.  et al. 2011. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365:1663–72 [Google Scholar]
  110. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB. 110.  et al. 1999. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N. Engl. J. Med. 340:23–30 [Google Scholar]
  111. Ramsey BW, Richardson MA. 111.  1992. Impact of sinusitis in cystic fibrosis. J. Allergy Clin. Immunol. 90:547–52 [Google Scholar]
  112. Ratjen F, Munck A, Kho P, Angyalosi G, Group ES. 112.  2010. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 65:286–91 [Google Scholar]
  113. Reznikov LR, Dong Q, Chen JH, Moninger TO, Park JM. 113.  et al. 2013. CFTR-deficient pigs display peripheral nervous system defects at birth. PNAS 110:3083–88 [Google Scholar]
  114. Riordan JR. 114.  2008. CFTR function and prospects for therapy. Annu. Rev. Biochem. 77:701–26 [Google Scholar]
  115. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R. 115.  et al. 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–73 [Google Scholar]
  116. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G. 116.  et al. 1989. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245:1059–65 [Google Scholar]
  117. Rommens JM, Zengerling S, Burns J, Melmer G, Kerem BS. 117.  et al. 1988. Identification and regional localization of DNA markers on chromosome 7 for the cloning of the cystic fibrosis gene. Am. J. Hum. Genet. 43:645–63 [Google Scholar]
  118. Rowe SM, Clancy JP. 118.  2009. Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development. BioDrugs 23:165–74 [Google Scholar]
  119. Rowe SM, Miller S, Sorscher EJ. 119.  2005. Cystic fibrosis. N. Engl. J. Med. 352:1992–2001 [Google Scholar]
  120. Ruiz FE, Clancy JP, Perricone MA, Bebok Z, Hong JS. 120.  et al. 2001. A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum. Gene Ther. 12:751–61 [Google Scholar]
  121. Rymut SM, Harker A, Corey DA, Burgess JD, Sun H. 121.  et al. 2013. Reduced microtubule acetylation in cystic fibrosis epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 305:L419–31 [Google Scholar]
  122. Sagel SD, Chmiel JF, Konstan MW. 122.  2007. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc. Am. Thorac. Soc. 4:406–17 [Google Scholar]
  123. Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M. 123.  et al. 2010. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 303:1707–15 [Google Scholar]
  124. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL. 124.  et al. 2003. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 290:1749–56 [Google Scholar]
  125. Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. 125.  2010. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am. J. Respir. Crit. Care Med. 182:627–32 [Google Scholar]
  126. Sanders DB, Hoffman LR, Emerson J, Gibson RL, Rosenfeld M. 126.  et al. 2010. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr. Pulmonol. 45:127–34 [Google Scholar]
  127. Sawicki GS, Sellers DE, Robinson WM. 127.  2009. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J. Cyst. Fibros. 8:91–96 [Google Scholar]
  128. Schuster A, Haliburn C, Döring G, Goldman MH. 128.  (Freedom Study Group) 2013. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 68:344–50 [Google Scholar]
  129. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I. 129.  et al. 2013. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13:653–58 [Google Scholar]
  130. Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB. 130.  1999. CFTR is a conductance regulator as well as a chloride channel. Physiol. Rev. 79:S145–66 [Google Scholar]
  131. Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T. 131.  et al. 2010. 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. 182:1262–72 [Google Scholar]
  132. Sermet-Gaudelus I, Renouil M, Fajac A, Bidou L, Parbaille B. 132.  et al. 2007. In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study. BMC Med. 5:5 [Google Scholar]
  133. Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. 133.  2015. Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. Clin. Otolaryngol. 40:16–21 [Google Scholar]
  134. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S. 134.  et al. 2013. Risk factors for bronchiectasis in children with cystic fibrosis. N. Engl. J. Med. 368:1963–70 [Google Scholar]
  135. Smyth A, Tan KH, Hyman-Taylor P, Mulheran M, Lewis S. 135.  et al. 2005. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial. Lancet 365:573–78 [Google Scholar]
  136. Sokol RJ, Durie PR. 136.  Cyst. Fibr. Found. Hepatobiliary Dis. Consen. Group 1999. Recommendations for management of liver and biliary tract disease in cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 28:Suppl. 1S1–13 [Google Scholar]
  137. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. 137.  et al. 2008. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J. Am. Diet. Assoc. 108:832–39 [Google Scholar]
  138. Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA. 138.  et al. 1995. CFTR as a cAMP-dependent regulator of sodium channels. Science 269:847–50 [Google Scholar]
  139. Tang L, Fatehi M, Linsdell P. 139.  2009. Mechanism of direct bicarbonate transport by the CFTR anion channel. J. Cyst. Fibros. 8:115–21 [Google Scholar]
  140. Tarran R, Trout L, Donaldson SH, Boucher RC. 140.  2006. Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J. Gen. Physiol. 127:591–604 [Google Scholar]
  141. Tiddens HAWM, De Boeck K, Clancy JP, Fayon M, Arets HGM. 141.  et al. 2015. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: the ALPINE study. J. Cyst. Fibros. 14:111–19 [Google Scholar]
  142. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M. 142.  et al. 2011. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch. Pediatr. Adolesc. Med. 165:847–56 [Google Scholar]
  143. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE. 143.  et al. 2014. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 2:361–68 [Google Scholar]
  144. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D. 144.  et al. 2009. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. PNAS 106:18825–30 [Google Scholar]
  145. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH. 145.  et al. 2011. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. PNAS 108:18843–48 [Google Scholar]
  146. Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M. 146.  et al. 2014. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci. Transl. Med. 6:246ra97 [Google Scholar]
  147. Vertex Pharm. 147.  2015. FDA approves ORKAMBI™ (lumacaftor/ivacaftor) - the first medicine to treat the underlying cause of cystic fibrosis for people ages 12 and older with two copies of the F508del mutation Press Release, July 2. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=920512 [Google Scholar]
  148. Vertex Pharm. 148.  2015. Vertex announces data from 12-week phase 2 safety study of VX-661 in combination with ivacaftor in people with cystic fibrosis who have two copies of the F508del mutation. Press Release, Mar. 23. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=902790 [Google Scholar]
  149. Vertex Pharm. 149.  2015. Vertex receives U.S. Food and Drug Administration approval of KALYDECO® (ivacaftor) for children with cystic fibrosis ages 2 to 5 who have specific mutations in the CFTR gene. Press Release, Mar. 18. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=902211 [Google Scholar]
  150. Vic P, Ategbo S, Turck D, Husson MO, Launay V. 150.  et al. 1998. Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis. Arch. Dis. Child. 78:536–39 [Google Scholar]
  151. von Rokitansky D. 151.  1842. Handbuch der speciellen pathologischen Anatomie, II Vienna: Braumuller & Seidel [Google Scholar]
  152. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X. 152.  et al. 2015. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 373:220–31 [Google Scholar]
  153. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ. 153.  et al. 2007. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87–91 [Google Scholar]
  154. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. 154.  2001. Cystic fibrosis. The Metabolic and Molecular Bases of Inherited Disease CR Scriver, AL Beaudet, WS Sly, D Valle, B Childs, et al 5121–88 New York: McGraw-Hill, 8th ed.. [Google Scholar]
  155. Welsh MJ, Smith AE, Zabner J, Rich DP, Graham SM. 155.  et al. 1994. Cystic fibrosis gene therapy using an adenovirus vector: in vivo safety and efficacy in nasal epithelium. Hum. Gene Ther. 5:209–19 [Google Scholar]
  156. Welsh MJ, Smith JJ. 156.  2001. cAMP stimulation of HCO3 secretion across airway epithelia. JOP 2:291–93 [Google Scholar]
  157. Whitehead A, Conway SP, Etherington C, Caldwell NA, Setchfield N, Bogle S. 157.  2002. Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. Eur. Respir. J. 19:303–9 [Google Scholar]
  158. 158. WHO (World Health Organ.) 2004. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS, Genoa, Italy, 19 June 2002 Rep., WHO, Geneva, Switz. [Google Scholar]
  159. Wilschanski M, Miller LL, Shoseyov D, Blau H, Rivlin J. 159.  et al. 2011. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur. Respir. J. 38:59–69 [Google Scholar]
  160. Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L. 160.  et al. 2003. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 349:1433–41 [Google Scholar]
  161. Xue X, Mutyam V, Tang L, Biswas S, Du M. 161.  et al. 2014. Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. Am. J. Respir. Cell Mol. Biol. 50:805–16 [Google Scholar]
  162. Zabner J, Couture LA, Gregory RJ, Graham SM, Smith AE, Welsh MJ. 162.  1993. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75:207–16 [Google Scholar]
  163. Zhou Z, Duerr J, Johannesson B, Schubert SC, Treis D. 163.  et al. 2011. The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. J. Cyst. Fibros. 10:Suppl. 2S172–82 [Google Scholar]
/content/journals/10.1146/annurev-genom-090314-050024
Loading
/content/journals/10.1146/annurev-genom-090314-050024
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error