Modern pathogenesis-based methods and development of new gene and cell-based methods for cystic fibrosis treatment

Cover Page

Cite item


Cystic fibrosis is a monogenic autosomal recessive disorder caused by mutations in CFTR gene. Until recent days, cystic fibrosis therapy was limited to symptomatic treatment of respiratory infections and malabsorption. In last years pathogenetic therapy of the disease received significant progress and premises for development of new methods of gene therapy came into sight. In the review, modern methods of cystic fibrosis treatment are considered, some of them are already used in the clinic (pathogenesis-based therapy with CFTR modulators), while the other part is only developing (gene therapy, including genome editing and cell therapy).

Full Text

Restricted Access

About the authors

S. A Smirnikhina

Research Centre for Medical Genetics


A. V Lavrov

Research Centre for Medical Genetics; N.I. Pirogov Russian National Research Medical University


  1. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur. Respir. Rev. 2013; 22: 58-65.
  2. Berger H.A., Anderson M.P., Gregory R.J. et al. Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel. J. Clin. Invest. 1991; 88: 1422-31.
  3. Choi J.Y., Muallem D., Kiselyov K. et al. Aberrant CFTR-dependent HCO3-transport in mutations associated with cystic fibrosis. Nature 2001; 410: 94-7.
  4. Cystic Fibrosis Foundation. Patient registry: annual data report, 2016. Bethesda, MD 2017, pdf.
  5. Lukacs G.L., Mohamed A., Kartner N. et al. Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP. EMBO J. 1994; 13: 6076-86.
  6. Van Goor F., Straley K.S., 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: L1117-30.
  7. O'Sullivan B.P., Freedman S.D. Cystic fibrosis. Lancet 2009; 373: 1891-904.
  8. Каширская Н.Ю., Капранов Н.И. Современные фармакотерапевтические подходы к лечению муковисцидоза. Фарматека 2014; 3: 38-43.
  9. Каширская Н.Ю., Капранов Н.И., Шерман В.Д. и др. Заместительная терапия ферментами поджелудочной железы при муковисцидозе. Педиатрия. Журнал им. Г.Н. Сперанского 2014; 93(4): 124-31.
  10. Красовский С.А., Амелина Е.Л., Кондратьева Е.И. и др. Медикаментозное лечение муковисцидоза в России: анализ данных национального регистра (2014). Пульмонология 2016; 25(5): 539-55.
  11. De Boeck K., Amaral M.D. Progress in therapies for cystic fibrosis. Lancet Respir. Med. 2016; 4(8): 662-74.
  12. McDonald C.M., Campbell C., Torricelli R.E. et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10101): 1489-98.
  13. Zainal Abidin N., Haq I.J., Gardner A.I. et al. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin. Pharmacother. 2017; 18(13): 1363-71.
  14. Van Goor F., Hadida S., Grootenhuis P.D. et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. PNAS USA 2009; 106(44): 18825-30.
  15. Ramsey B.W., Davies J., McElvaney N.G. et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 2011; 365(18): 1663-72.
  16. Eckford P.D., Li C., Ramjeesingh M. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J. Biol. Chem. 2012; 287(44): 36639-49.
  17. FDA Approves Ivacaftor for Five Splice Mutations, https://www.cff. org/News/News-Archive/2017/FDA-Approves-Ivacaftor-for-Five-Splice-Mutations/.
  18. Flume P.A., Liou T.G., Borowitz D.S. et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142(3): 718-24.
  19. Mijnders M., Kleizen B., Braakman I. Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis. Curr. Opin. Pharmacol. 2017; 34: 83-90.
  20. Ren H.Y., Grove D.E., De La Rosa O. et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol. Biol. Cell 2013; 24(19): 3016-24.
  21. Clancy J.P., Rowe S.M., Accurso F.J. et al. 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(1): 12-8.
  22. Kopeikin Z., Yuksek Z., Yang H.Y. et al. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J. Cyst. Fibros. 2014; 13(5): 508-14.
  23. Deeks E.D. Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis. Drugs 2016; 76(12): 1191-201.
  24. Highlights of prescribing information, uspi_lumacaftor_ivacaftor.pdf.
  25. Milla C.E., Ratjen F., Marigowda G. et al. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am. J. Respir. Crit. Care Med. 2017; 195(7): 912-20.
  26. Boyle M.P., Bell S.C., Konstan M.W. et al. 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.
  27. Rowe S.M., McColley S.A., Rietschel E. et al. Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Ann. Am. Thorac. Soc. 2017; 14(2): 213-9.
  28. Rowe S.M., Daines C., Ringshausen F.C. et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N. Engl. J. Med. 2017; 377(21): 2024-35.
  29. Vertex Initiates First Phase 3 Study of VX-659, Tezacaftor and Ivacaftor as a Triple Combination Regimen for People with Cystic Fibrosis. Acquire Media, e136394a-d5a2-4db2-afe0-054b3d65f064.
  30. Schneider E.K., Azad M.A., Han M.L. et al. An “Unlikely” Pair: The Antimicrobial Synergy of Polymyxin B in Combination with the Cystic Fibrosis Transmembrane Conductance Regulator Drugs KALYDECO and ORKAMBI. ACS Infect. Dis. 2016; 2(7): 478-88.
  31. Jordan C.L., Noah T.L., Henry M.M. Therapeutic challenges posed by critical drug-drug interactions in cystic fibrosis. Pediatr. Pulmonol. 2016; 51(S44): S61-70.
  32. Sabusap C.M., Wang W., McNicholas C.M. et al. Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases. JCI Insight 2016; 1(14): pii: e86581.
  33. Амелина Е.Л., Красовский С.А., Усачёва М.В. и др. Патогенетическое лечение муковисцидоза: первый клинический случай в России. Пульмонология 2017; 27(2): 298-301.
  34. Schneider E.K., Reyes-Ortega F., Li J. et al. Can Cystic Fibrosis Patients Finally Catch a Breath With Lumacaftor/Ivacaftor? Clin. Pharmacol. Ther. 2017; 101(1): 130-41.
  35. Amaral M.D. Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients. J. Intern. Med. 2015; 277(2): 155-66.
  36. Griesenbach U., Alton E.W. Moving forward: cystic fibrosis gene therapy. Hum. Mol. Genet. 2013; 22(R1): R52-8.
  37. Griesenbach U., Pytel K.M., Alton E.W. Cystic fibrosis gene therapy in the UK and elsewhere. Hum. Gene Ther. 2015; 26: 266-75.
  38. Dhooghe B., Haaf J.B., Noel S. et al. Strategies in early clinical development for the treatment of basic defects of cystic fibrosis. Expert Opin. Investig. Drugs 2016; 25(4): 423-36.
  39. National Library of Medicine at the National Institutes of Health,
  40. Boucher R.C., Knowles M.R., Johnson L.G. et al. Gene therapy for cystic fibrosis using E1-deleted adenovirus: a phase I trial in the nasal cavity. The University of North Carolina at Chapel Hill. Hum. Gene Ther. 1994; 5(5): 615-39.
  41. Knowles M.R., Hohneker K.W., Zhou Z. et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 1995; 333(13): 823-31.
  42. Caplen N.J., Alton E.W., Middleton P.G. et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat. Med. 1995; 1(1): 39-46.
  43. Sorscher E.J., Logan J.J., Frizzell R.A. et al. Gene therapy for cystic fibrosis using cationic liposome mediated gene transfer: a phase I trial of safety and efficacy in the nasal airway. Hum. Gene Ther. 1994; 5(10): 1259-77.
  44. Zuckerman J.B., Robinson C.B., McCoy K.S. et al. A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis. Hum. Gene Ther. 1999; 10(18): 2973-85.
  45. Flotte T., Carter B., Conrad C. et al. A phase I study of an adenoassociated virus-CFTR gene vector in adult CF patients with mild lung disease. Hum. Gene Ther. 1996; 7(9): 1145-59.
  46. Wagner J.A., Moran M.L., Messner A.H. et al. A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. Hum. Gene Ther. 1998; 9(6): 889-909.
  47. Wagner J.A., Reynolds T., Moran M.L. et al. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet 1998; 351(9117): 1702-3.
  48. Wagner J.A., Messner A.H., Moran M.L. et al. Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 1999; 109(2 Pt 1): 266-74.
  49. Aitken M.L., Moss R.B., Waltz D.A. et al. A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease. Hum. Gene Ther. 2001; 12(15): 1907-16.
  50. Wagner J.A., Nepomuceno I.B., Messner A.H. et al. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum. Gene Ther. 2002; 13(11): 1349-59.
  51. Flotte T.R., Zeitlin P.L., Reynolds T.C. et al. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum. Gene Ther. 2003; 14(11): 1079-88.
  52. Flotte T.R., Schwiebert E.M., Zeitlin P.L. et al. Correlation between DNA transfer and cystic fibrosis airway epithelial cell correction after recombinant adeno-associated virus serotype 2 gene therapy. Hum. Gene Ther. 2005; 16(8): 921-8.
  53. Moss R.B., Rodman D., Spencer L.T. et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 2004; 125(2): 509-21.
  54. Moss R.B., Milla C., Colombo J. et al. Repeated aerosolized AAVCFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum. Gene Ther. 2007; 18(8): 726-32.
  55. McLachlan G., Ho L.P., Davidson-Smith H. et al. Laboratory and clinical studies in support of cystic fibrosis gene therapy using pCMV-CFTR-DOTAP. Gene Ther. 1996; 3(12): 1113-23.
  56. Alton E.W., Stern M., Farley R. et al. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 1999; 353(9157): 947-54.
  57. Alton E.W., Armstrong D.K., Ashby D. 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(9): 684-91.
  58. Alton E.W.F.W., Armstrong D.K., Ashby D. et al. A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis. Efficacy Mech. Eval. 2016; 3(5). doi: 10.3310/eme03050.
  59. Beumer W., Swildens J., Henig N. et al. QR-010, an RNA therapy, restores CFTR function using in vitro and in vivo models of dF508 CFTR. J. Cyst. Fibros. 2015; 14(S1): S1.
  60. Brinks V., Lipinska K., Koppelaar M. et al. QR-010 treatment for cystic fibrosis: assessing the airway-mucus barrier in delivery. Pediatric Pulmonology 2015; 50(S41): 271.
  61. Brinks V., Lipinska K., Koppelaar M. et al. QR-010 penetrates the CF-like mucus barrier in vitro and in vivo. Journal of Cystic Fibrosis 2016; 15(S1): S31.
  62. Vannucci L., Lai M., Chiuppesi F. et al. Viral vectors: a look back and ahead on gene transfer technology. New Microbiol. 2013; 36(1): 1-22.
  63. Schuster B.S., Kim A.J., Kays J.C. et al. Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors. Mol. Ther. 2014; 22(8): 1484-93.
  64. Myint M., Limberis M., Bell P. et al. In Vivo Evaluation of Adeno-Associated Virus Gene Transfer in Airways of Mice with Acute or Chronic Respiratory Infection. Hum. Gene Ther. 2014; 25(11): 966-76.
  65. Alton E.W., Beekman J.M., Boyd A.C. et al. Preparation for a first-inman lentivirus trial in patients with cystic fibrosis. Thorax 2017; 72(2): 137-47.
  66. Noone P.G., Hohneker K.W., Zhou Z. et al. Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol. Ther. 2000; 1(1): 105-14.
  67. Eluforsen Clinical trials: Study 002, eluforsen-npd-study-002/.
  68. Maeder M.L., Gersbach C.A. Genome-editing Technologies for Gene and Cell Therapy. Mol. Ther. 2016; 24(3): 430-46.
  69. Salsman J., Dellaire G. Precision genome editing in the CRISPR era. Biochem. Cell Biol. 2017; 95(2): 187-201.
  70. Kim Y.G., Cha J., Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. PNAS USA 1996; 93(3): 1156-60.
  71. Maeder M.L., Thibodeau-Beganny S., Osiak A. et al. Rapid “open-source” engineering of customized zinc-finger nucleases for highly efficient gene modification. Mol. Cell 2008; 31(2): 294-301.
  72. Lee C.M., Flynn R., Hollywood J.A. et al. Correction of the AF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Gene by Zinc-Finger Nuclease Homology-Directed Repair. Biores. Open Access 2012; 1(3): 99-108.
  73. Bednarski C., Tomczak K., Vom Hövel B. et al. Targeted Integration of a Super-Exon into the CFTR Locus Leads to Functional Correction of a Cystic Fibrosis Cell Line Model. PLoS One 2016; 11(8): e0161072.
  74. Ramalingam S., London V., Kandavelou K. et al. Generation and genetic engineering of human induced pluripotent stem cells using designed zinc finger nucleases. Stem Cells Dev. 2013; 22(4): 595-610.
  75. Crane A.M., Kramer P., Bui J.H. et al. Targeted correction and restored function of the CFTR gene in cystic fibrosis induced pluripotent stem cells. Stem Cell Reports 2015; 4(4): 569-77.
  76. Samson M., Labbe O., Mollereau C. et al. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 1996; 35(11): 3362-7.
  77. Cermak T., Doyle E.L., Christian M. et al. Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res. 2011; 39(12): e82.
  78. Camarasa M.V., Galvez V.M. Robust method for TALEN-edited correction of pF508del in patient-specific induced pluripotent stem cells. Stem Cell Res. Ther. 2016; 7: 26.
  79. Suzuki S., Sargent R.G., Illek B. et al. TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs. Mol. Ther. Nucleic Acids 2016; 5: e273.
  80. Merkert S., Bednarski C., Göhring G. et al. Generation of a gene-corrected isogenic control iPSC line from cystic fibrosis patient-specific iPSCs homozygous for p.Phe508del mutation mediated by TALENs and ssODN. Stem Cell Res. 2017; 23: 95-7.
  81. Банников А.В., Лавров А.В. CRISPR/CAS9 - король геномного редактирования. Молекулярная биология 2017; 51(4): 582-94.
  82. Валетдинова К.Р., Устьянцева Е.И., Елисафенко Е.А. и др. Инструменты геномной инженерии, предназначенные для создания изогенной клеточной модели бокового амиотрофического склероза. Медицинская генетика 2015; 14(6): 3-9.
  83. Zhang F., Wen Y., Guo X. CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum. Mol. Genet. 2014; 23(R1): R40-6.
  84. Schwank G., Koo B.K., 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.
  85. Firth A.L., Menon T., Parker G.S. et al. Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs. Cell Rep. 2015; 12(9): 1385-90.
  86. Hollywood J.A., Lee C.M., Scallan M.F. et al. Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene. Sci. Rep. 2016; 6: 32230.
  87. Sanz D.J., Hollywood J.A., Scallan M.F. et al. Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA. PLoS One 2017; 12(9): e0184009.
  88. Murphy S.V., Atala A. Cell therapy for cystic fibrosis. J. Tissue Eng. Regen. Med. 2015; 9(3): 210-23.
  89. Wecht S., Rojas M. Mesenchymal stem cells in the treatment of chronic lung disease. Respirology 2016; 21(8): 1366-75.
  90. Weiss D.J., Chambers D., Giangreco A. et al. An official American Thoracic Society workshop report: stem cells and cell therapies in lung biology and diseases. Ann. Am. Thorac. Soc. 2015; 12(4): S79-97.
  91. Dogan A. Embryonic Stem Cells in Development and Regenerative Medicine. Adv. Exp. Med. Biol. 2018; 1079; 1-15.
  92. Hayes M., Masterson C., Devaney J. et al. Therapeutic efficacy of human mesenchymal stromal cells in the repair of established ventilator-induced lung injury in the rat. Anesthesiology 2015; 122(2): 363-73.
  93. Wilson J.G., Liu K.D., Zhuo H. et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir. Med. 2015; 3(1): 24-32.
  94. Khoury O., Barrios C., Ortega V. et al. Immunomodulatory Cell Therapy to Target Cystic Fibrosis Inflammation. Am. J. Respir. Cell Mol. Biol. 2018; 58(1): 12-20.
  95. Carbone A., Castellani S., Favia M. et al. Correction of defective CFTR/ENaC function and tightness of cystic fibrosis airway epithelium by amniotic mesenchymal stromal (stem) cells. J. Cell. Mol. Med. 2014; 18(8): 1631-43.
  96. Griesenbach U., Alton E.W. Progress in gene and cell therapy for cystic fibrosis lung disease. Curr. Pharm. Des. 2012; 18(5): 642-62.
  97. Wang G., Bunnell B.A., Painter R.G. et al. Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. PNAS USA 2005; 102(1): 186-91.
  98. Takahashi K., Tanabe K., Ohnuki M. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5): 861-72.
  99. Wong A.P., Bear C.E., Chin S. et al. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotechnol. 2012; 30(9): 876-82.
  100. McCauley K.B., Hawkins F., Serra M. et al. Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling. Cell Stem Cell 2017; 20(6): 844-57.
  101. Rosen C., Shezen E., Aronovich A. et al. Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice. Nat. Med. 2015; 21(8): 869-79.
  102. Duchesneau P., Besla R., Derouet M.F. et al. Partial Restoration of CFTR Function in cftr-Null Mice following Targeted Cell Replacement Therapy. Mol. Ther. 2017; 25(3): 654-65.
  103. Cohen-Cymberknoh M., Shoseyov D., Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am. J. Respir. Crit. Care Med. 2011; 183(11): 1463-71.

Copyright (c) 2018 PJSC Human Stem Cells Institute

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 57156 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies