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Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis

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Abstract

Cystic fibrosis (CF) is a life-limiting disease caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) activity. The recent advent of the FDA-approved CFTR modulator drug ivacaftor, alone or in combination with lumacaftor or tezacaftor, has enabled treatment of the majority of patients suffering from CF. Even before the identification of the CFTR gene, gene therapy was put forward as a viable treatment option for this genetic condition. However, initial enthusiasm has been hampered as CFTR gene delivery to the lungs has proven to be more challenging than expected. This review covers the contemporary clinical and scientific knowledge base for small molecule CFTR modulator drug therapy, gene delivery vectors and CRISPR/Cas9 gene editing and highlights the prospect of these technologies for future treatment options.

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References

  1. Griesenbach U, Pytel KM, Alton EW. Cystic fibrosis gene therapy in the UK and elsewhere. Hum Gene Ther. 2015;26:266–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kleizen B, Braakman I, de Jonge HR. Regulated trafficking of the CFTR chloride channel. Eur J Cell Biol. 2000;79:544–56.

    Article  CAS  PubMed  Google Scholar 

  3. Sheppard DN, Welsh MJ. Structure and function of the CFTR chloride channel. Physiol Rev. 1999;79(1 Suppl):S23–45.

    Article  CAS  PubMed  Google Scholar 

  4. Schneider EK, Huang JX, Carbone V, Baker M, Azad MA, Cooper MA, et al. Drug-drug plasma protein binding interactions of ivacaftor. J Mol Recognit. 2015;28:339–48.

    Article  CAS  PubMed  Google Scholar 

  5. Tizzano EF, Buchwald M. CFTR expression and organ damage in cystic fibrosis. Ann Interna Med. 1995;123:305–8.

    Article  CAS  Google Scholar 

  6. O’Sullivan BP, Flume P. The clinical approach to lung disease in patients with cystic fibrosis. Semin Respir Crit Care Med. 2009;30:505–13.

    Article  PubMed  Google Scholar 

  7. Solomon M. Cystic fibrosis-update on diagnosis and treatment from cystic fibrosis etiology, diagnosisn and treatments. In: Leatte PN, editors Treatments for cystic fibrosis; 2009.

  8. Schneider EK, Reyes-Ortega F, Li J, Velkov T. Can cystic fibrosis patients finally catch a breath with lumacaftor/ivacaftor? Clin Pharmacol Ther. 2017;101:130–41.

    Article  CAS  PubMed  Google Scholar 

  9. Gill DR, Hyde SC. Delivery of genes into the CF airway. Thorax. 2014;69:962–4.

    Article  PubMed  Google Scholar 

  10. Conway SP, Pond MN, Hamnett T, Watson A. Compliance with treatment in adult patients with cystic fibrosis. Thorax. 1996;51:29–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Worldwide CF https://www.cfww.org (2018).

  12. Dean M, Santis G. Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Hum Genet. 1994;93:364–8.

    Article  CAS  PubMed  Google Scholar 

  13. Goodman BE, Percy WH. CFTR in cystic fibrosis and cholera: from membrane transport to clinical practice. Adv Physiol Educ. 2005;29:75–82.

    Article  PubMed  Google Scholar 

  14. Griesenbach U, Alton EW. Moving forward: cystic fibrosis gene therapy. Hum Mol Genet. 2013;22(R1):R52–8.

    Article  CAS  PubMed  Google Scholar 

  15. Griesenbach U, Alton EW. Current status and future directions of gene and cell therapy for cystic fibrosis. BioDrugs. 2011;25:77–88.

    Article  CAS  PubMed  Google Scholar 

  16. Griesenbach U, Geddes DM, Alton EW. Advances in cystic fibrosis gene therapy. Curr Opin Pulm Med. 2004;10:542–6.

    Article  CAS  PubMed  Google Scholar 

  17. Davis PB, Yasothan U, Kirkpatrick P. Ivacaftor. Nat Rev. Drug Discov. 2012;11:349–50.

    Article  CAS  PubMed  Google Scholar 

  18. Sala MA, Jain M. Tezacaftor for the treatment of cystic fibrosis. Expert Rev Respir Med. 2018:12;725–32.

  19. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9:737–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sheridan C. Gene therapy finds its niche. Nat Biotechnol. 2011;29:121–8.

    Article  CAS  PubMed  Google Scholar 

  21. Aiuti A. Advances in gene therapy for ADA-deficient SCID. Curr Opin Mol Ther. 2002;4:515–22.

    CAS  PubMed  Google Scholar 

  22. Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012;120:3635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cooney AL, McCray PB, Jr, Sinn PL. Cystic fibrosis gene therapy: looking back, looking forward. Genes. 2018;9 pii: E538. https://doi.org/10.3390/genes9110538.

    Article  PubMed Central  CAS  Google Scholar 

  24. Stern M, Ulrich K, Geddes DM, Alton EW. Poly (D, L-lactide-co-glycolide)/DNA microspheres to facilitate prolonged transgene expression in airway epithelium in vitro, ex vivo and in vivo. Gene Ther. 2003;10:1282–8.

    Article  CAS  PubMed  Google Scholar 

  25. Schuster BS, Kim AJ, Kays JC, Kanzawa MM, Guggino WB, Boyle MP, et al. Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors. Mol Ther. 2014;22:1484–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia E, Munegowda MA, Cao H, Hu J. Lung gene therapy-How to capture illumination from the light already present in the tunnel. Genes Dis. 2014;1:40–52.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yonemitsu Y, Kitson C, Ferrari S, Farley R, Griesenbach U, Judd D, et al. Efficient gene transfer to airway epithelium using recombinant Sendai virus. Nat Biotechnol. 2000;18:970–3.

    Article  CAS  PubMed  Google Scholar 

  28. Mitomo K, Griesenbach U, Inoue M, Somerton L, Meng C, Akiba E, et al. Toward gene therapy for cystic fibrosis using a lentivirus pseudotyped with Sendai virus envelopes. Mol Ther. 2010;18:1173–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Joseph PM, O’Sullivan BP, Lapey A, Dorkin H, Oren J, Balfour R, et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Hum Gene Ther. 2001;12:1369–82.

    Article  CAS  PubMed  Google Scholar 

  30. Perricone MA, Morris JE, Pavelka K, Plog MS, O’Sullivan BP, Joseph PM, et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum Gene Ther. 2001;12:1383–94.

    Article  CAS  PubMed  Google Scholar 

  31. Harvey BG, Leopold PL, Hackett NR, Grasso TM, Williams PM, Tucker AL, et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J Clin Investig. 1999;104:1245–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bellon G, Michel-Calemard L, Thouvenot D, Jagneaux V, Poitevin F, Malcus C, et al. Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum Gene Ther. 1997;8:15–25.

    Article  CAS  PubMed  Google Scholar 

  33. Crystal RG, McElvaney NG, Rosenfeld MA, Chu CS, Mastrangeli A, Hay JG, et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet. 1994;8:42–51.

    Article  CAS  PubMed  Google Scholar 

  34. Hay JG, McElvaney NG, Herena J, Crystal RG. Modification of nasal epithelial potential differences of individuals with cystic fibrosis consequent to local administration of a normal CFTR cDNA adenovirus gene transfer vector. Hum Gene Ther. 1995;6:1487–96.

    Article  CAS  PubMed  Google Scholar 

  35. Knowles MR, Hohneker KW, Zhou Z, Olsen JC, Noah TL, Hu PC, et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. New Engl J Med. 1995;333:823–31.

    Article  CAS  PubMed  Google Scholar 

  36. Walters RW, Grunst T, Bergelson JM, Finberg RW, Welsh MJ, Zabner J. Basolateral localization of fiber receptors limits adenovirus infection from the apical surface of airway epithelia. J Biol Chem. 1999;274:10219–26.

    Article  CAS  PubMed  Google Scholar 

  37. Vidovic D, Carlon MS, da Cunha MF, Dekkers JF, Hollenhorst MI, Bijvelds MJ, et al. rAAV-CFTRDeltaR rescues the cystic fibrosis phenotype in human intestinal organoids and cystic fibrosis mice. Am J Respir Crit Care Med. 2016;193:288–98.

    Article  CAS  PubMed  Google Scholar 

  38. Vidovic D, Gijsbers R, Quiles-Jimenez A, Dooley J, Van den Haute C, Van, et al. Noninvasive imaging reveals stable transgene expression in mouse airways after delivery of a nonintegrating recombinant adeno-associated viral vector. Hum Gene Ther. 2016;27:60–71.

    Article  CAS  PubMed  Google Scholar 

  39. Wagner JA, Reynolds T, Moran ML, Moss RB, Wine JJ, Flotte TR, et al. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet. 1998;351:1702–3.

    Article  CAS  PubMed  Google Scholar 

  40. Johnson LG, Olsen JC, Naldini L, Boucher RC. Pseudotyped human lentiviral vector-mediated gene transfer to airway epithelia in vivo. Gene Ther. 2000;7:568–74.

    Article  CAS  PubMed  Google Scholar 

  41. Burney TJ, Davies JC. Gene therapy for the treatment of cystic fibrosis. Appl Clin Genet. 2012;5:29–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Gene therapy of primary T cell immunodeficiencies. Gene. 2013;525:170–3.

    Article  CAS  PubMed  Google Scholar 

  43. Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. J Am Med Assoc. 2015;313:1550–63.

    Article  CAS  Google Scholar 

  44. Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman NK, et al. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 2012;186:846–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee TW, Matthews DA, Blair GE. Novel molecular approaches to cystic fibrosis gene therapy. Biochem J. 2005;387(Pt 1):1–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hyde SC, Pringle IA, Abdullah S, Lawton AE, Davies LA, Varathalingam A, et al. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol. 2008;26:549–51.

    Article  CAS  PubMed  Google Scholar 

  47. Griesenbach U, Ferrari S, Geddes DM, Alton EW. Gene therapy progress and prospects: cystic fibrosis. Gene Ther. 2002;9:1344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maclachlan TK, Lukason M, Collins M, Munger R, Isenberger E, Rogers C, et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther. 2011;19:326–34.

    Article  CAS  PubMed  Google Scholar 

  49. Ruiz FE, Clancy JP, Perricone MA, Bebok Z, Hong JS, Cheng SH, et al. A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum Gene Ther. 2001;12:751–61.

    Article  CAS  PubMed  Google Scholar 

  50. Alton EW, Boyd AC, Porteous DJ, Davies G, Davies JC, Griesenbach U, et al. A phase I/IIa safety and efficacy study of nebulized liposome-mediated gene therapy for cystic fibrosis supports a multidose trial. Am J Respir Crit Care Med. 2015;192:1389–92.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Alton E, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, et al. 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;3:684–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. https://www.boehringer-ingelheim.com/press-release/new-partnership-develop-gene-therapy-cystic-fibrosis? (2018).

  53. Marangi M, Pistritto G. Innovative therapeutic strategies for cystic fibrosis: moving forward to CRISPR technique. Front Pharmacol. 2018;9:396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang H, Wang H, Shivalila CS, Cheng AW, Shi L, Jaenisch R. One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell. 2013;154:1370–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13:653–8.

    Article  CAS  PubMed  Google Scholar 

  57. Fan Z, Perisse IV, Cotton CU, Regouski M, Meng Q, Domb C, et al. A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene. JCI insight. 2018;3 pii: 123529.

  58. Crane AM, Kramer P, Bui JH, Chung WJ, Li XS, Gonzalez-Garay ML, et al. Targeted correction and restored function of the CFTR gene in cystic fibrosis induced pluripotent stem cells. Stem Cell Rep. 2015;4:569–77.

    Article  CAS  Google Scholar 

  59. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Martiniano SL, Sagel SD, Zemanick ET. Cystic fibrosis: a model system for precision medicine. Curr Opin Pediatr. 2016;28:312–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, 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;4:107–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fajac I, De Boeck K. New horizons for cystic fibrosis treatment. Pharmacol Ther. 2017;170:205–11.

    Article  CAS  PubMed  Google Scholar 

  64. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013–23.

    Article  CAS  PubMed  Google Scholar 

  65. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. Tezacaftor/Ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Rrespir Crit Care Med. 2018;197:214–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX-445-Tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J med. 2018;379:1612–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, et al. VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379:1599–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther. 2015;145:19–34.

    Article  CAS  PubMed  Google Scholar 

  69. De Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016;4:662–74.

    Article  PubMed  CAS  Google Scholar 

  70. Bosch B, De Boeck K. Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell. Eur J Pediatr. 2016;175:1–8.

    Article  PubMed  Google Scholar 

  71. Cholon DM, Esther, Charles R, Gentzsch, Martina. Efficacy of lumacaftor-ivacaftor for the treatment of Cystic Fibrosis patients homozygous for the F508del-CFTR mutation. Expert Rev Precis Med Drug Dev. 2016;1:235–43.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Masson A, Schneider-Futschik EK, Baatallah N, Nguyen-Khoa T, Girodon E, Hatton A et al. Predictive factors for lumacaftor/ivacaftor clinical response. J Cyst Fibros. 2019;18:368–74.

    Article  CAS  PubMed  Google Scholar 

  73. FDA. Sponsor Briefing Document: ORKAMBI (Lumacaftor/Ivacaftor) for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. In: commiteeFACBMV-FP-Ada, editors. VERTEX Pharmaceuticals Incorporated; 2015. p. 98.

  74. Schneider EK Cytochrome P450 3A4 induction: lumacaftor versus ivacaftor potentially resulting in significantly reduced plasma concentration of ivacaftor. Drug Metab Lett. 2018;12:71–4. https://doi.org/10.2174/1872312812666180328105259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schneider EK, Reyes-Ortega F, Wilson JW, Kotsimbos T, Keating D, Li J, et al. Development of HPLC and LC-MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J Chromatogr B, Analyt Technol Biomed Life Sci. 2016;1038:57–62.

    Article  CAS  Google Scholar 

  76. EMA. Assessment report ORKAMBI (ivacaftor/lumacaftor) European medicines agency EMEA/H/C/003954/0000, 2015.

  77. Cholon DM, Quinney NL, Fulcher ML, Esther CR,Jr, Das J, Dokholyan NV. et al. Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6:246ra96

    Article  PubMed  PubMed Central  Google Scholar 

  78. Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM. et al. Some gating potentiators, including VX-770, diminish DeltaF508-CFTR functional expression. Sci Transl Med. 2014;6:246ra97

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Foundation CF. Drug Development Pipeline. https://www.cff.org/Trials/Pipeline: cff.org. 2017.

  80. De Boeck K, Davies JC. Where are we with transformational therapies for patients with cystic fibrosis? Current Opin Pharmacol. 2017;34:70–75.

    Article  CAS  Google Scholar 

  81. Cholon DM, Gentzsch M, Recent progress in translational cystic fibrosis research using precision medicine strategies. J Cyst Fibros. 2018;17:S52–60. https://doi.org/10.1016/j.jcf.2017.09.005.

    Article  PubMed  Google Scholar 

  82. Patel AK, Kaczmarek JC, Bose S, Kauffman KJ, Mir F, Heartlein MW, et al. Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. Adv Mater. 2019;31:e1805116. https://doi.org/10.1002/adma.201805116.

    Article  CAS  Google Scholar 

  83. De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros. 2014;13:403–9.

    Article  PubMed  CAS  Google Scholar 

  84. http://www.cftr.info/about-cf/cftr-mutations/the-six-classes-of-cftr-defects/. Classification of CFTR mutations (2018).

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  1. Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia

    Elena K. Schneider-Futschik PhD

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The author has received the Vertex Cystic Fibrosis Research Award from the ‘Thoracic Society of Australia and New Zealand (TSANZ)’, which was sponsored by Vertex Pharmaceuticals.

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Schneider-Futschik, E.K. Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis. Gene Ther 26, 354–362 (2019). https://doi.org/10.1038/s41434-019-0092-5

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