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Gene Therapy Progress and Prospects: Cystic fibrosis

Gene Therapy volume 9, pages 1344–1350 (2002)Cite this article

Abstract

Since the cloning of the cystic fibrosis gene (CFTR) in 1989, 18 clinical trials have been carried out, including five in the 2 years reviewed here. Most trials demonstrated proof-of-principle for gene transfer to the airway. However, gene transfer efficiency with each of the three gene transfer agents (adenovirus (Ad), adeno-associated virus 2 (AAV2) and cationic liposomes) was low, and most likely insufficient to achieve clinical benefit. Here, we will review the clinical and pre-clinical progress for the last 2 years (2000–2001) and briefly speculate on future prospects for the next 2 in CF gene therapy.

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References

  1. Noone PG 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: 105–114

    Article  CAS  PubMed  Google Scholar 

  2. Ruiz FE et al. A clinical inflammatory syndrome attributable to aerosolised lipid-DNA administration in cystic fibrosis Hum Gene Ther 2001 12: 751–761

    Article  CAS  PubMed  Google Scholar 

  3. Hyde SC et al. Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis Gene Therapy 2000 7: 1156–1165

    Article  CAS  PubMed  Google Scholar 

  4. Perricone MA 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: 1383–1394

    Article  CAS  PubMed  Google Scholar 

  5. Aitken ML et al. A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease Hum Gene Ther 2001 12: 1907–1916

    Article  CAS  PubMed  Google Scholar 

  6. Ferrari S et al. Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium Gene Therapy 2001 8: 1380–1386

    Article  CAS  PubMed  Google Scholar 

  7. Sanders NN, Van Rompaey E, De Smedt SC, Demeester J . Structural alterations of gene complexes by cystic fibrosis sputum Am J Respir Crit Care Med 2001 164: 486–493

    Article  CAS  PubMed  Google Scholar 

  8. Perricone MA et al. Inhibitory effect of cystic fibrosis sputum on adenovirus-mediated gene transfer in cultured epithelial cells Hum Gene Ther 2000 11: 1997–2008

    Article  CAS  PubMed  Google Scholar 

  9. Virella-Lowell I et al. Inhibition of recombinant adeno-associated virus (rAAV) transduction by bronchial secretions from cystic fibrosis patients Gene Therapy 2000 7: 1783–1789

    Article  CAS  PubMed  Google Scholar 

  10. Sanders NN et al. Cystic fibrosis sputum: a barrier to the transport of nanospheres. Am J Respir Crit Care Med 2000 162: 1905–1911

    CAS  Google Scholar 

  11. Pickles RJ et al. Retargeting the coxsackievirus and adenovirus receptor to the apical surface of polarized epithelial cells reveals the glycocalyx as a barrier to adenovirus-mediated gene transfer J Virol 2000 74: 6050–6057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang G et al. Increasing epithelial junction permeability enhances gene transfer to airway epithelia in vivo Am J Respir Cell Mol Biol 2000 22: 129–138

    Article  PubMed  Google Scholar 

  13. Chu Q et al. EGTA enhancement of adenovirus-mediated gene transfer to mouse tracheal epithelium in vivo Hum Gene Ther 2001 12: 455–467

    Article  CAS  PubMed  Google Scholar 

  14. Man Y et al. Loss of epithelial integrity resulting from E-cadherin dysfunction predisposes airway epithelial cells to adenoviral infection Am J Respir Cell Mol Biol 2000 23: 610–617

    Article  CAS  PubMed  Google Scholar 

  15. Coyne CB, Kelly MM, Boucher RC, Johnson LG . Enhanced epithelial gene transfer by modulation of tight junctions with sodium caprate Am J Respir Cell Mol Biol 2000 23: 602–609

    Article  CAS  PubMed  Google Scholar 

  16. Croyle MA, Cheng X, Sandhu A, Wilson JM . Development of novel formulations that enhance adenoviral-mediated gene expression in the lung in vitro and in vivo Mol Ther 2001 4: 22–28

    Article  CAS  PubMed  Google Scholar 

  17. Weiss DJ et al. Perfluorochemical liquid enhances adeno-associated virus-mediated transgene expression in lung Mol Ther 2000 2: 624–630

    Article  CAS  PubMed  Google Scholar 

  18. Das A, Niven R . Use of perfluorocarbon (Fluorinert) to enhance reporter gene expression following intratracheal instillation into the lungs of Balb/c mice: implications for nebulized delivery of plasmids J Pharm Sci 2001 90: 1336–1344

    Article  CAS  PubMed  Google Scholar 

  19. Ziady AG et al. Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor Mol Ther 2002 5: 413–419

    Article  CAS  PubMed  Google Scholar 

  20. Jost PJ et al. A novel peptide, THALWHT, for the targeting of human airway epithelia FEBS Lett 2001 489: 263–269

    Article  CAS  PubMed  Google Scholar 

  21. Zhang L, Collins PL, Boucher RC, Pickles RJ . Respiratory syncytial virus (RSV) infects ciliated cells of airway epithelium via the lumenal membrane Pediat Pulmonol 2001 244

  22. Yonemitsu Y et al. Efficient gene transfer to airway epithelium using recombinant Sendai virus Nat Biotechnol 2000 18: 970–973

    Article  CAS  PubMed  Google Scholar 

  23. Walters RW et al. Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer J Biol Chem 2001 276: 20610–20616

    Article  CAS  PubMed  Google Scholar 

  24. Zabner J et al. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer J Virol 2000 74: 3852–3858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Halbert CL et al. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes J Virol 2000 74: 1524–1532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duan D, Yue Y, Engelhardt JF . Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison Mol Ther 2001 4: 383–391

    Article  CAS  PubMed  Google Scholar 

  27. Ostedgaard LS et al. CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo Proc Natl Acad Sci USA 2002 99: 3093–3098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pickles RJ, Hirsh AJ, Gerard RJ, Boucher RC . Retargeting Ad5 fibers to bradykinin receptors expressed on the lumenal surface of human airway epithelium Pediat Pulmonol 2001 22: 247

    Google Scholar 

  29. Drapkin PT et al. Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia J Clin Invest 2000 105: 589–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kreda SM, Pickles RJ, Lazarowski ER, Boucher RC . G-protein-coupled receptors as targets for gene transfer vectors using natural small-molecules ligands Nat Biotechnol 2000 18: 635–640

    Article  CAS  PubMed  Google Scholar 

  31. Wang G et al. Human coronavirus 229E infects polarized airway epithelia from the apical surface J Virol 2000 74: 9234–9239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Slepushkin VA et al. Infection of human airway epithelia with H1N1, H2N2 and H3N2 influenza A virus strains Mol Ther 2001 3: 395–402

    Article  CAS  PubMed  Google Scholar 

  33. Kobinger GP, Weiner DJ, Yu QC, Wilson JM . Filovirus-pseudotyped lentiviral vector can efficiently and stably transduce airway epithelia in vivo Nat Biotechnol 2001 19: 225–230

    Article  CAS  PubMed  Google Scholar 

  34. Chirmule N et al. Readministration of adenovirus vector in nonhuman primate lungs by blockade of CD40-CD40 ligand interactions J Virol 2000 74: 3345–3352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kolb M et al. Budesonide enhances repeated gene transfer and expression in the lung with adenoviral vectors Am J Respir Crit Care Med 2001 164: 866–872

    Article  CAS  PubMed  Google Scholar 

  36. Croyle MA, Chirmule N, Zhang Y, Wilson JM . ‘Stealth’ adenovirus blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung J Virol 2001 75: 4792–4801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yew NS et al. Reduced inflammatory responses to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs Mol Ther 2000 1: 255–262

    Article  CAS  PubMed  Google Scholar 

  38. Pollard H et al. Ca2+-sensitive cytosolic nucleases prevent efficient delivery to the nucleus of injected plasmids J Gene Med 2001 3: 153–164

    Article  CAS  PubMed  Google Scholar 

  39. Duan D et al. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus J Clin Invest 2000 105: 1573–1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yan Z et al. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors J Virol 2002 76: 2043–2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yan Z et al. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors Griesenbach U et al. Cytoplasmic deposition of NFκB decoy oligonucleotides is insufficient to inhibit bleomycin induced pulmonary inflammation. Gene Therapy 2002 (in press).

  42. Cartier R, Reszka R . Utilization of synthetic peptides containing nuclear localization signals for nonviral gene transfer systems Gene Therapy 2002 9: 157–167

    Article  CAS  PubMed  Google Scholar 

  43. Klink DT, Chao S, Glick MC, Scanlin TF . Nuclear translocation of lactosylated poly-L-lysine/cDNA complex in cystic fibrosis airway epithelial cells Mol Ther 2001 3: 831–841

    Article  CAS  PubMed  Google Scholar 

  44. Cassivi SD et al. Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs J Heart Lung Transplant 2000 19: 984–994

    Article  CAS  PubMed  Google Scholar 

  45. Scaria A et al. Adenoviral vector expressing ICP47 inhibits adenovirus-specific cytotoxic T lymphocytes in nonhuman primates Mol Ther 2000 2: 505–514

    Article  CAS  PubMed  Google Scholar 

  46. Gill DR et al. Increased persistence of lung gene expression using plasmids containing the ubiquitin C or elongation factor 1α promoter Gene Therapy 2001 8: 1539–1546

    Article  CAS  PubMed  Google Scholar 

  47. Yew NS et al. High and sustained transgene expression in vivo from plasmid vector containing a hybrid ubiquitin promoter Mol Ther 2001 4: 75–82

    Article  CAS  PubMed  Google Scholar 

  48. Stoll SM et al. Epstein-Barr virus/human vector provides high-level, long-term expression of alpha1-antitrypsin in mice Mol Ther 2001 4: 122–129

    Article  CAS  PubMed  Google Scholar 

  49. Huertas D, Howe S, McGuigan A, Huxley C . Expression of the human CFTR gene from episomal oriP-EBNA1-YACs in mouse cells Hum Mol Genet 2000 9: 617–629

    Article  CAS  PubMed  Google Scholar 

  50. Fox E et al. Towards nucleic acid transfer to the airway epithelium via the systemic route Mol Ther 2001 3: S197

    Article  Google Scholar 

  51. Koehler DR et al. Targeting transgene expression for cystic fibrosis gene therapy Mol Ther 2001 4: 58–65

    Article  CAS  PubMed  Google Scholar 

  52. Boyle MP et al. In utero AAV-mediated gene transfer to rabbit pulmonary epithelium Mol Ther 2001 4: 115–121

    Article  CAS  PubMed  Google Scholar 

  53. Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KML . Re-expression following readministration of an adenoviral vector in adult mice after initial in utero adenoviral administration Mol Ther 2000 2: 374–380

    Article  CAS  PubMed  Google Scholar 

  54. Larson JE et al. Gene transfer into the fetal primate: evidence for the secretion of transgene product Mol Ther 2000 2: 631–639

    Article  CAS  PubMed  Google Scholar 

  55. Larson JE et al. CFTR modulates lung secretory cell proliferation and differentiation Am J Physiol Lung Cell Mol Physiol 2000 279: L333–L341

    Article  CAS  PubMed  Google Scholar 

  56. Griesenbach U et al. Conversion of wild-type CFTR to the G551D mutation in primary rat hepatocytes using RNA/DNA oligonucleotides Pediat Pulmonol 2001 252

  57. Goncz KK et al. Expression of (F508 CFTR in normal lung after site-specific modification of CFTR sequences by SFHR Gene Therapy 2001 8: 961–965

    Article  CAS  PubMed  Google Scholar 

  58. Lambert G et al. Control of cystic fibrosis transmembrane conductance regulator expression by BAP31 J Biol Chem 2001 276: 20340–20345

    Article  CAS  PubMed  Google Scholar 

  59. Liu X et al. Partial correction of endogenous (F508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing Nat Biotechnol 2002 20: 47–52

    Article  CAS  PubMed  Google Scholar 

  60. Liu X et al. Partial correction of endogenous (F508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing Gersting S et al. Magnetofection of permanent and primary human airway epithelial cells. Mol Ther 2001; 3: Abstr. 1017.

  61. Krause DS et al. Mutli-organ, multi-lineage engraftment by a single bone marrow-derived sem cell Cell 2001 105: 369–377

    Article  CAS  PubMed  Google Scholar 

  62. Ye L et al. Regulated expression of the human CFTR gene in epithelial cells Mol Ther 2001 3: 723–733

    Article  CAS  PubMed  Google Scholar 

  63. Ye L et al. Regulated expression of the human CFTR gene in epithelial cells Jiang Q, Li Z, Zhang Y, Engelhardt JF. Development of a ferret model of the cystic fibrosis. Pediat Pulmonol 2000; 20 (Suppl.): Abstr. 164.

  64. Mouchel N et al. The sheep genome contributes to localization of control elements in a human gene with complex regulatory mechanisms Genomics 2001 76: 9–13

    Article  CAS  PubMed  Google Scholar 

  65. Mouchel N et al. The sheep genome contributes to localization of control elements in a human gene with complex regulatory mechanisms Rooney C et al. Laser induced fluorescence bronchoscopy for the detection of gene transfer. Mol Ther 2001; 3: Abstr. 1152.

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Authors and Affiliations

  1. Department of Gene Therapy, National Heart and Lung Institute, Imperial College, Faculty of Medicine, London, UK

    U Griesenbach, S Ferrari, D M Geddes & E W F W Alton

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  1. U Griesenbach
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  2. S Ferrari
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  3. D M Geddes
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  4. E W F W Alton
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Griesenbach, U., Ferrari, S., Geddes, D. et al. Gene Therapy Progress and Prospects: Cystic fibrosis. Gene Ther 9, 1344–1350 (2002). https://doi.org/10.1038/sj.gt.3301791

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