Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2006:259–268. doi: 10.1007/978-1-59259-963-9_28

Gene Therapy for Lung Diseases

Eric WFW Alton, Jane C Davies 2, Duncan M Geddes 3
Editors: Marschall S Runge*, Cam Patterson*
PMCID: PMC7121178

Abstract

Gene therapy is under development for a variety of lung disease, both those caused by single gene defects, such as cystic fibrosis and α1-antitrypsin deficiency, and multifactorial diseases such as cancer, asthma, lung fibrosis, and ARDS. Both viral and nonviral approaches have been explored, the major limitation to the former being the inability to repeatedly administer, which renders this approach perhaps more applicable to conditions requiring single administration, such as cancer. Progress in development and clinical trials in each of these diseases is reviewed, together with some potential newer approaches for the future.

Key Words: α1-antitrypsin deficiency, ARDS, asthma, cysticfibrosis, fibrosis, lung cancer, lung inflammation, lung transplantation, pulmonary edema

Selected References

  1. 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;353:947–954. doi: 10.1016/S0140-6736(98)06532-5. [DOI] [PubMed] [Google Scholar]
  2. Armstrong D.S., Grimwood K., Carzino R., Carlin J.B., Olinsky A., Phelan P.D. Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ. 1995;310:1571–1572. doi: 10.1136/bmj.310.6994.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bellon G., Michel-Calemard L., Thouvenot D., 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. doi: 10.1089/hum.1997.8.1-15. [DOI] [PubMed] [Google Scholar]
  4. Bischoff J.R., Kirn D.H., Williams A., et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996;274:373–376. doi: 10.1126/science.274.5286.373. [DOI] [PubMed] [Google Scholar]
  5. Boasquevisque C.H., Mora B.N., Bernstein M., et al. Ex vivo liposome-mediated gene transfer to lung isografts. J Thorac Cardiovasc Surg. 1998;115:38–44. doi: 10.1016/S0022-5223(98)70440-4. [DOI] [PubMed] [Google Scholar]
  6. Boasquevisque C.H., Mora B.N., Boglione M., et al. Liposome-mediated gene transfer in rat lung transplantation: a comparison between the in vivo and ex vivo approaches. J Thorac Cardiovasc Surg. 1999;117:8–14. doi: 10.1016/S0022-5223(99)70463-0. [DOI] [PubMed] [Google Scholar]
  7. 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;5:615–639. doi: 10.1089/hum.1994.5.5-615. [DOI] [PubMed] [Google Scholar]
  8. Bou-Gharios G., Wells D.J., Lu Q.L., Morgan J.E., Partridge T. Differential expression and secretion of alpha1 anti-trypsin between direct DNA injection and implantation of transfected myoblast. Gene Ther. 1999;6:1021–1029. doi: 10.1038/sj.gt.3300933. [DOI] [PubMed] [Google Scholar]
  9. Brigham K.L., Lane K.B., Meyrick B., et al. Transfection of nasal mucosa with a normal α1-antitrypsin gene in α1-antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther. 2000;11:1023–1032. doi: 10.1089/10430340050015338. [DOI] [PubMed] [Google Scholar]
  10. Brisson M., He Y., Li S., Yang J.P., Huang L. A novel T7 RNA polymerase autogene for efficient cytoplasmic expression of target genes. Gene Ther. 1999;6:263–270. doi: 10.1038/sj.gt.3300827. [DOI] [PubMed] [Google Scholar]
  11. Canonico A.E., Conary J.T., Meyrick B.O., Brigham K.L. Aerosol and intravenous transfection of human alpha 1-antitrypsin gene to lungs of rabbits. Am J Respir Cell Mol Biol. 1994;10:24–29. doi: 10.1165/ajrcmb.10.1.8292378. [DOI] [PubMed] [Google Scholar]
  12. 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. NatMed. 1995;1:39–46. doi: 10.1038/nm0195-39. [DOI] [PubMed] [Google Scholar]
  13. Cassivi S.D., Cardella J.A., Fischer S., Liu M., Slutsky A.S., Keshavjee S. Transtracheal gene transfection of donor lungs prior to organ procurement increases transgene levels at reperfusion and following transplantation. J Heart Lung Transplant. 1999;18:1181–1188. doi: 10.1016/S1053-2498(99)00095-9. [DOI] [PubMed] [Google Scholar]
  14. Chadwick S.L., Kingston H.D., Stern M., et al. Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/ DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers. Gene Ther. 1997;4:937–942. doi: 10.1038/sj.gt.3300481. [DOI] [PubMed] [Google Scholar]
  15. Chirmule N., Truneh A., Haecker S.E., et al. Repeated administration of adenoviral vectors in lungs of human CD4 transgenic mice treated with a nondepleting CD4 antibody. J Immunol. 1999;163:448–455. [PubMed] [Google Scholar]
  16. Coakley R.J., Taggart C., O’Neill S., McElvaney N.G. Alpha 1-antitrypsin deficiency: biological answers to clinical questions. Am J Med Sci. 2001;321:33–41. doi: 10.1097/00000441-200101000-00006. [DOI] [PubMed] [Google Scholar]
  17. Conary J.T., Parker R.E., Christman B.W., et al. Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest. 1994;93:1834–1840. doi: 10.1172/JCI117169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Crystal R.G., McElvaney N.G., Rosenfeld M.A., 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. doi: 10.1038/ng0994-42. [DOI] [PubMed] [Google Scholar]
  19. Koehler D.R., Hannam V., Belcastro R., et al. Targeting transgene expression for cystic fibrosis gene therapy. Mol Ther. 2001;4:58–65. doi: 10.1006/mthe.2001.0412. [DOI] [PubMed] [Google Scholar]
  20. Dennehy K.C., Bigatello L.M. Pathophysiology of the acute respiratory distress syndrome. Int Anesthesiol Clin. 1999;37:1–13. doi: 10.1097/00004311-199903730-00004. [DOI] [PubMed] [Google Scholar]
  21. Dow S.W., Schwarze J., Heath T.D., Potter T.A., Gelfand E.W. Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice. Hum Gene Ther. 1999;10:1905–1914. doi: 10.1089/10430349950017266. [DOI] [PubMed] [Google Scholar]
  22. Duan D., Yue Y., Yan Z., Yang J., Engelhardt J.F. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest. 2000;105:1573–1587. doi: 10.1172/JCI8317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Dumasius V., Sznajder J.I., Azzam Z.S., et al. Beta(2)-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats. Circ Res. 2001;89:907–914. doi: 10.1161/hh2201.100204. [DOI] [PubMed] [Google Scholar]
  24. Engelhardt J.F., Yankaskas J.R., Ernst S.A., et al. Submucosal glands are the predominant site of CFTR expression in the human bronchus. Nat Genet. 1992;2:240–248. doi: 10.1038/ng1192-240. [DOI] [PubMed] [Google Scholar]
  25. Engelhardt J.F., Zepeda M., Cohn J.A., Yankaskas J.R., Wilson J.M. Expression of the cystic fibrosis gene in adult human lung. J Clin Invest. 1994;93:737–749. doi: 10.1172/JCI117028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Epperly M., Bray J., Kraeger S., et al. Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy. Gene Ther. 1998;5:196–208. doi: 10.1038/sj.gt.3300580. [DOI] [PubMed] [Google Scholar]
  27. Factor P. Role and regulation of lung Na,K-ATPase. Cell Mol Biol. 2001;47:347–361. [PubMed] [Google Scholar]
  28. Factor P., Dumasius V., Saldias F., Brown L.A., Sznajder J.I. Adenovirusmediated transfer of an Na+/K+-ATPase beta1 subunit gene improves alveolar fluid clearance and survival in hyperoxic rats. Hum Gene Ther. 2000;11:2231–2242. doi: 10.1089/104303400750035753. [DOI] [PubMed] [Google Scholar]
  29. Fasbender A., Lee J.H., Walters R.W., Moninger T.O., Zabner J., Welsh M.J. Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo. J Clin Invest. 1998;102:184–193. doi: 10.1172/JCI2732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Fenske D.B., MacLachlan I., Cullis P.R. Long-circulating vectors for the systemic delivery of genes. Curr Opin Mol Ther. 2001;3:153–158. [PubMed] [Google Scholar]
  31. Ferrari S., Kitson C., Farley R., et al. Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium. Gene Ther. 2001;8:1380–1386. doi: 10.1038/sj.gt.3301525. [DOI] [PubMed] [Google Scholar]
  32. Fonseca C., Abraham D., Black C.M. Lung fibrosis. Springer Semin Immunopathol. 1999;21:453–474. doi: 10.1007/s002810000036. [DOI] [PubMed] [Google Scholar]
  33. Fujiwara T., Grimm E.A., Mukhopadhyay T., Zhang W.W., Owen-Schaub L.B., Roth J.A. Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res. 1994;54:2287–2291. [PubMed] [Google Scholar]
  34. Gahery-Segard H., Molinier-Frenkel V., Le Boulaire C., et al. Phase I trial of recombinant adenovirus gene transfer in lung cancer: longitudinal study of the immune responses to transgene and viral products. J Clin Invest. 1997;100:2218–2226. doi: 10.1172/JCI119759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Gan K.H., Veeze H.J., van den Ouweland A.M., et al. A cystic fibrosis mutation associated with mild lung disease. N Engl J Med. 1995;333:95–99. doi: 10.1056/NEJM199507133330204. [DOI] [PubMed] [Google Scholar]
  36. Griesenbach U., Chonn A., Cassady R., et al. Comparison between intratracheal and intravenous administration of liposome-DNA complexes for cystic fibrosis lung gene therapy. Gene Ther. 1998;5:181–188. doi: 10.1038/sj.gt.3300562. [DOI] [PubMed] [Google Scholar]
  37. Gill D.R., Smyth S.E., Goddard C.A., et al. Increased persistence of lung gene expression using plasmids containing the ubiquitin C or elongation factor 1alpha promoter. Gene Ther. 2001;8:1539–1546. doi: 10.1038/sj.gt.3301561. [DOI] [PubMed] [Google Scholar]
  38. Gill D.R., Southern K.W., Mofford K.A., et al. A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 1997;4:199–209. doi: 10.1038/sj.gt.3300391. [DOI] [PubMed] [Google Scholar]
  39. Grosse S., Tremeau-Bravard A., Aron Y., Briand P., Fajac I. Intracellular ratelimiting steps of gene transfer using glycosylated polylysines in cystic fibrosis airway epithelial cells. Gene Ther. 2002;9:1000–1007. doi: 10.1038/sj.gt.3301768. [DOI] [PubMed] [Google Scholar]
  40. Harvey B.-G., Leopold P.L., Hackett N.R., et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J Clin Invest. 1999;104:1245–1255. doi: 10.1172/JCI7935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Heise C., Sampson-Johannes A., Williams A., McCormick F., Von Hoff D.D., Kirn D.H. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med. 1997;3:639–645. doi: 10.1038/nm0697-639. [DOI] [PubMed] [Google Scholar]
  42. Hogan S.P., Foster P.S., Tan X., Ramsay A.J., Mucosal I.- 12 gene delivery inhibits allergic airways disease and restores local antiviral immunity. Eur J Immunol. 1998;28:413–423. doi: 10.1002/(SICI)1521-4141(199802)28:02<413::AID-IMMU413>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  43. Houtmeyers E., Gosselink R., Gayan-Ramirez G., Decramer M. Regulation of mucociliary clearance in health and disease. Eur Respir J. 1999;13:1177–1788. doi: 10.1034/j.1399-3003.1999.13e39.x. [DOI] [PubMed] [Google Scholar]
  44. Hyde S.C., Southern K.W., Gileadi U., et al. Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 2000;7:1156–1165. doi: 10.1038/sj.gt.3301212. [DOI] [PubMed] [Google Scholar]
  45. Inoue S., Suzuki M., Nagashim Y., et al. Transfer of heme oxygenase 1 cDNA by a replication-deficient adenovirus enhances interleukin 10 production from alveolar macrophages that attenuates lipopolysaccharide-induced acute lung injury in mice. Hum Gene Ther. 2001;12:967–979. doi: 10.1089/104303401750195926. [DOI] [PubMed] [Google Scholar]
  46. Itano H., Zhang W., Ritter J.H., McCarthy T.J., Mohanakumar T., Patterson G.A. Adenovirus-mediated gene transfer of human interleukin 10 ameliorates reperfusion injury of rat lung isografts. J Thorac Cardiovasc Surg. 2000;120:947–956. doi: 10.1067/mtc.2000.109240. [DOI] [PubMed] [Google Scholar]
  47. Johnson L.G., Boyles S.E., Wilson J., Boucher R.C. Normalization of raised sodium absorption and raised calcium-mediated chloride secretion by adenovirus-mediated expression of cystic fibrosis transmembrane conductance regulator in primary human cystic fibrosis airway epithelial cells. J Clin Invest. 1995;95:1377–1382. doi: 10.1172/JCI117789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Kitson C., Angel B., Judd D., et al. The extra-and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium. Gene Ther. 1999;6:534–546. doi: 10.1038/sj.gt.3300840. [DOI] [PubMed] [Google Scholar]
  49. Knowles M., Gatzy J., Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med. 1981;305:1489–1495. doi: 10.1056/NEJM198112173052502. [DOI] [PubMed] [Google Scholar]
  50. Knowles M.R., Noone P.G., Hohneker K., et al. A double-blind, placebo controlled, dose ranging study to evaluate the safety and biological efficacy of the lipid-DNA complex GR213487B in the nasal epithelium of adult patients with cystic fibrosis. Hum Gene Ther. 1998;9:249–269. doi: 10.1089/hum.1998.9.2-249. [DOI] [PubMed] [Google Scholar]
  51. Kolb M., Inman M., Margetts P.J., Galt T., Gauldie J. Budesonide enhances repeated gene transfer and expression in the lung with adenoviral vectors. Am J Respir Crit Care Med. 2001;164:866–872. doi: 10.1164/ajrccm.164.5.2008066. [DOI] [PubMed] [Google Scholar]
  52. Kolb M., Margetts P.J., Galt T., et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med. 2001;163:770–777. doi: 10.1164/ajrccm.163.3.2006084. [DOI] [PubMed] [Google Scholar]
  53. Kumasaka T., Quinlan W.M., Doyle N.A., et al. Role of the intercellular adhesion molecule-1 (ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice. J Clin Invest. 1996;97:2362–2369. doi: 10.1172/JCI118679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Kuwano K., Hagimoto N., Kawasaki M., et al. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest. 1999;104:13–19. doi: 10.1172/JCI5628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Lack G., Renz H., Saloga J., et al. Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization. J Immunol. 1994;152:2546–2554. [PubMed] [Google Scholar]
  56. Lechardeur D., Sohn K.J., Haardt M., et al. Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer. Gene Ther. 1999;6:482–497. doi: 10.1038/sj.gt.3300867. [DOI] [PubMed] [Google Scholar]
  57. Lee E.R., Marshall J., Siegel C.S., et al. Detailed analysis of structures and formulations of cationic lipids for efficient gene transfer to the lung. Hum Gene Ther. 1996;7:1701–1717. doi: 10.1089/hum.1996.7.14-1701. [DOI] [PubMed] [Google Scholar]
  58. Lee J.C., Laydon J.T., McDonnell P.C., et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739–746. doi: 10.1038/372739a0. [DOI] [PubMed] [Google Scholar]
  59. Lee N.A., Gelfand E.W., Lee J.J. Pulmonary T cells and eosinophils: cocon-spirators or independent triggers of allergic respiratory pathology? J Allergy Clin Immunol. 2001;107:945–957. doi: 10.1067/mai.2001.116002. [DOI] [PubMed] [Google Scholar]
  60. Leroy P., Slos P., Homann H., et al. Cancer immunotherapy by direct in vivo transfer of immunomodulatory genes. Res Immunol. 1998;149:681–684. doi: 10.1016/S0923-2494(99)80038-8. [DOI] [PubMed] [Google Scholar]
  61. Mal H., Dehoux M., Sleiman C., et al. Early release of proinflammatory cytokines after lung transplantation. Chest. 1998;113:645–651. doi: 10.1378/chest.113.3.645. [DOI] [PubMed] [Google Scholar]
  62. McCormick F. Interactions between adenovirus proteins and the p53 pathway: the development of ONYX-015. Semin Cancer Biol. 2000;10:453–459. doi: 10.1006/scbi.2000.0336. [DOI] [PubMed] [Google Scholar]
  63. McLachlan G., Stevenson B.J., Davidson D.J., Porteous D.J. Bacterial DNA is implicated in the inflammatory response to delivery of DNA/DOTAP to mouse lungs. Gene Ther. 2000;7:384–392. doi: 10.1038/sj.gt.3301097. [DOI] [PubMed] [Google Scholar]
  64. Middleton P.G., Geddes D.M. Alton EWFW. Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium. Eur Respir J. 1994;7:2050–2056. doi: 10.1183/09031936.94.07030442. [DOI] [PubMed] [Google Scholar]
  65. Mora B.N., Boasquevisque C.H., Boglione M., et al. Transforming growth factor-beta1 gene transfer ameliorates acute lung allograft rejection. J Thorac Cardiovasc Surg. 2000;119:913–920. doi: 10.1016/S0022-5223(00)70086-9. [DOI] [PubMed] [Google Scholar]
  66. Moss R.B., Aitken M., Clancy J., et al. A multi-centre, double-blind, placebo-controlled phase II study of aerosolised TGAAVCF in cystic fibrosis patients with mild lung disease. Pediatr Pulmonol. 2002;24:250. [Google Scholar]
  67. Mukherjee S., Haenel T., Himbeck R., et al. Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation. Cancer Gene Ther. 2000;7:663–670. doi: 10.1038/sj.cgt.7700133. [DOI] [PubMed] [Google Scholar]
  68. Munkonge F.M., Hillery E., Griesenbach U., Geddes D.M. Alton EWFW. Isolation of a putative nuclear import DNA shuttle protein. Mol Biol Cell. 1998;9:187A. [Google Scholar]
  69. Nakao A., Fujii M., Matsumura R., et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest. 1999;104:5–11. doi: 10.1172/JCI6094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Nemunaitis J., Cunningham C., Buchanan A., et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther. 2001;8:746–759. doi: 10.1038/sj.gt.3301424. [DOI] [PubMed] [Google Scholar]
  71. Nemunaitis J., Swisher S.G., Timmons T., et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small cell lung cancer. J Clin Oncol. 2000;18:609–622. doi: 10.1200/JCO.2000.18.3.609. [DOI] [PubMed] [Google Scholar]
  72. Niidome T., Huang L. Gene therapy progress and prospects: nonviral vectors. Gene Ther. 2002;9:1647–1652. doi: 10.1038/sj.gt.3301923. [DOI] [PubMed] [Google Scholar]
  73. Nishikawa M., Huang L. Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum Gene Ther. 2001;12:861–870. doi: 10.1089/104303401750195836. [DOI] [PubMed] [Google Scholar]
  74. Parsons D.W., Grubb B.R., Johnson L.G., Boucher R.C. Enhanced in vivo airway gene transfer via transient modification of host barrier properties with a surface-active agent. Hum Gene Ther. 1998;9:2661–2672. doi: 10.1089/hum.1998.9.18-2661. [DOI] [PubMed] [Google Scholar]
  75. Patient Registry 1994 . Annual Data Report. Cystic Fibrosis Foundation: Bethesda, MD; 1995. [Google Scholar]
  76. Perricone M.A., Rees D.D., Sacks C.R., Smith K.A., Kaplan J.M., St George J.A. Inhibitory effect of cystic fibrosis sputum on adenovirus-mediated gene transfer in cultured epithelial cells. Hum Gene Ther. 2000;11:1997–2008. doi: 10.1089/10430340050143426. [DOI] [PubMed] [Google Scholar]
  77. Pickles R.J., Fahrner J.A., Petrella J.M., Boucher R.C., Bergelson J.M. 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. doi: 10.1128/JVI.74.13.6050-6057.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Pierce J.A. Alpha1-antitrypsin augmentation therapy. Chest. 1997;112:872–874. doi: 10.1378/chest.112.4.872. [DOI] [PubMed] [Google Scholar]
  79. Plank C., Mechtler K., Szoka F.C., Jr, Wagner E. Activation of the complement system by synthetic DNA complexes: A potential barrier for intravenous gene delivery. Hum Gene Ther. 1996;7:1437–1446. doi: 10.1089/hum.1996.7.12-1437. [DOI] [PubMed] [Google Scholar]
  80. Plank C., Schillinger U., Scherer F., et al. The magnetofection method: Using magnetic force to enhance gene delivery. Biol Chem. 2003;384:737–747. doi: 10.1515/BC.2003.082. [DOI] [PubMed] [Google Scholar]
  81. Porteous D.J., Dorin J.R., McLachlan G., et al. Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 1997;4:210–218. doi: 10.1038/sj.gt.3300390. [DOI] [PubMed] [Google Scholar]
  82. Quinonez R., Sutton R.E. Lentiviral vectors for gene delivery into cells. DNA Cell Biol. 2002;21:937–951. doi: 10.1089/104454902762053873. [DOI] [PubMed] [Google Scholar]
  83. Raczka E., Kukowska-Latallo J.F., Rymaszewski M., Chen C., Baker J.R., Jr. The effect of synthetic surfactant Exosurf on gene transfer in mouse lung in vivo. Gene Ther. 1998;5:1333–1339. doi: 10.1038/sj.gt.3300752. [DOI] [PubMed] [Google Scholar]
  84. Rogy M.A., Auffenberg T., Espat N.J., et al. Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. J Exp Med. 1995;181:2289–2293. doi: 10.1084/jem.181.6.2289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Rom W.N., Hay J.G., Lee T.C., Jiang Y., Tchou-Wong K.-M. Molecular and genetic aspects of lung cancer. Am J Respir Crit Care Med. 2000;161:1355–1367. doi: 10.1164/ajrccm.161.4.9908012. [DOI] [PubMed] [Google Scholar]
  86. Romanczuk H., Galer C.E., Zabner J., Barsomian G., Wadsworth S.C., O’Riordan C.R. Modification of an adenoviral vector with biologically selected peptides: a novel strategy for gene delivery to cells of choice. Hum Gene Ther. 1999;10:2615–2626. doi: 10.1089/10430349950016654. [DOI] [PubMed] [Google Scholar]
  87. Rosenfeld M.A., Siegfried W., Yoshimura K., et al. Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science. 1991;252:431–434. doi: 10.1126/science.2017680. [DOI] [PubMed] [Google Scholar]
  88. Roth J.A., Nguyen D., Lawrence D.D., et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nat Med. 1996;2:985–991. doi: 10.1038/nm0996-985. [DOI] [PubMed] [Google Scholar]
  89. Saylors R.L., III, Wall D.A. Expression of human alpha 1 antitrypsin in murine hematopoietic cells in vivo after retrovirus-mediated gene transfer. Mol Genet Metab. 1998;63:198–204. doi: 10.1006/mgme.1997.2665. [DOI] [PubMed] [Google Scholar]
  90. Schmid R.A., Stammberger U., Hillinger S., et al. Fas ligand gene transfer combined with low dose cyclosporine A reduces acute lung allograft rejection. Transpl Int. 2000;13(Suppl1):S324–S328. doi: 10.1007/s001470050353. [DOI] [PubMed] [Google Scholar]
  91. Schuler M., Herrmann R., De Greve J.L., et al. Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol. 2001;19:1750–1758. doi: 10.1200/JCO.2001.19.6.1750. [DOI] [PubMed] [Google Scholar]
  92. Schuler M., Rochlitz C., Horowitz J.A., et al. A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer. Hum Gene Ther. 1998;9:2075–2082. doi: 10.1089/hum.1998.9.14-2075. [DOI] [PubMed] [Google Scholar]
  93. Schwarze J., Hamelmann E., Cieslewicz G., et al. Local treatment with IL-12 is an effective inhibitor of airway hyperresponsiveness and lung eosinophilia after airway challenge in sensitized mice. J Allergy Clin Immunol. 1998;102:86–93. doi: 10.1016/S0091-6749(98)70058-2. [DOI] [PubMed] [Google Scholar]
  94. Schwarzt D.A., Quinn T.J., Thorne P.S., Sayeed S., Yi A.K., Krieg A.M. CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest. 1997;100:68–73. doi: 10.1172/JCI119523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Scott S.D., Marples B., Hendry J.H., et al. A radiation-controlled molecular switch for use in gene therapy of cancer. Gene Ther. 2000;7:1121–1125. doi: 10.1038/sj.gt.3301223. [DOI] [PubMed] [Google Scholar]
  96. Seiler M.P., Luner P., Moninger T.O., Karp P.H., Keshavjee S., Zabner J. Thixotropic solutions enhance viral-mediated gene transfer to airway epithelia. Am J Respir Cell Mol Biol. 2002;27:133–140. doi: 10.1165/ajrcmb.27.2.4793. [DOI] [PubMed] [Google Scholar]
  97. Sime P.J., O’Reilly K.M. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol. 2001;99:308–319. doi: 10.1006/clim.2001.5008. [DOI] [PubMed] [Google Scholar]
  98. Smythe W.R. Prodrug/drug sensitivity gene therapy: current status. Curr Oncol Rep. 2000;2:17–22. doi: 10.1007/s11912-000-0006-z. [DOI] [PubMed] [Google Scholar]
  99. Snyder R.O. Adeno-associated virus-mediated gene delivery. J Gene Med. 1999;1:166–175. doi: 10.1002/(SICI)1521-2254(199905/06)1:3<166::AID-JGM34>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  100. Snyder E.L., Dowdy S.F. Protein/peptide transduction domains: potential to deliver large DNA molecules into cells. Curr Opin Mol Ther. 2001;3:147–152. [PubMed] [Google Scholar]
  101. 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;5:1259–1277. doi: 10.1089/hum.1994.5.10-1259. [DOI] [PubMed] [Google Scholar]
  102. Stecenko A.A., Brigham K.L. Gene therapy progress and prospects: alpha-1 antitrypsin. Gene Ther. 2003;10:95–99. doi: 10.1038/sj.gt.3301947. [DOI] [PubMed] [Google Scholar]
  103. Sterman D.H., Treat J., Litzky L.A., et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localised malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther. 1998;9:1083–1092. doi: 10.1089/hum.1998.9.7-1083. [DOI] [PubMed] [Google Scholar]
  104. Stern M., Caplen N.J., Browning J.E., et al. The effects of mucolytic agents on gene transfer across a CF sputum barrier in vitro. Gene Ther. 1998;5:91–98. doi: 10.1038/sj.gt.3300556. [DOI] [PubMed] [Google Scholar]
  105. Stern M., Munkonge F.M., Caplen N.J., et al. Quantitative fluorescence measurements of chloride secretion in native airway epithelium from CF and non-CF subjects. Gene Ther. 1995;2:766–774. [PubMed] [Google Scholar]
  106. Stern M., Ulrich K., Robinson C., et al. Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema. Gene Ther. 2000;7:960–966. doi: 10.1038/sj.gt.3301193. [DOI] [PubMed] [Google Scholar]
  107. Suda T., D’Ovidio F., Daddi N., Ritter J.H., Mohanakumar T., Patterson G.A. Recipient intramuscular gene transfer of active transforming growth factor-beta1 attenuates acute lung rejection. Ann Thorac Surg. 2001;71:1651–1656. doi: 10.1016/S0003-4975(01)02528-0. [DOI] [PubMed] [Google Scholar]
  108. Suissa S., Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol. 2001;107:937–944. doi: 10.1067/mai.2001.115653. [DOI] [PubMed] [Google Scholar]
  109. Sumner S.G., Pringle I.A., Varathalingam A., Gill D.R., Hyde S.C. Use of electroporation to increase plasmid DNA transfer into epithelial cells of the respiratory tract. Mol Ther. 2003;7:S67. [Google Scholar]
  110. Swisher S.G., Roth J.A., Nemunaitis J., et al. Adenovirus-mediated p53 gene transfer in advanced non-small cell lung cancer. J Natl Cancer Inst. 1999;91:763–771. doi: 10.1093/jnci/91.9.763. [DOI] [PubMed] [Google Scholar]
  111. Taylor W., Gokay K.E., Capaccio C., Davis E., Glucksberg M., Dean D.A. The effects of cyclic stretch on gene transfer in alveolar epithelial cells. Mol Ther. 2003;7:542–549. doi: 10.1016/S1525-0016(03)00041-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Thomas C.E., Ehrhardt A., Kay M.A. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4:346–358. doi: 10.1038/nrg1066. [DOI] [PubMed] [Google Scholar]
  113. Tursz T., Cesne A.L., Baldeyrou P., et al. Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients. J Natl Cancer Inst. 1996;88:1857–1863. doi: 10.1093/jnci/88.24.1857. [DOI] [PubMed] [Google Scholar]
  114. van Heekeren A., Ferkol T., Tosi M. Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on gene transfer to airway epithelial cells in mice. Gene Ther. 1998;5:345–351. doi: 10.1038/sj.gt.3300593. [DOI] [PubMed] [Google Scholar]
  115. von der Leyen H.E., Gibbons G.H., Morishita R., et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial %5cell nitric oxide synthase gene. Proc Natl Acad Sci USA. 1995;92:1137–1141. doi: 10.1073/pnas.92.4.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. 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;13:1349–1359. doi: 10.1089/104303402760128577. [DOI] [PubMed] [Google Scholar]
  117. Wagner J.A., Reynolds T., Moran M.L., et al. Efficient and persistent gene transfer ofAAV-CFTR in maxillary sinus. Lancet. 1998;351:1702–1703. doi: 10.1016/S0140-6736(05)77740-0. [DOI] [PubMed] [Google Scholar]
  118. Walters R.W., Duan D., Engelhardt J.F., Welsh M.J. Incorporation of adeno-asso-ciated virus in a calcium phosphate coprecipitate improves gene transfer to airway epithelia in vitro and in vivo. J Virol. 2000;74:535–540. doi: 10.1128/JVI.74.1.535-540.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Walters R.W., Grunst T., Bergelson J.M., Finberg R.W., Welsh M.J., Zabner J. Basolateral localization of fiber receptors limits adenovirus infection from the apical surface of airway epithelia. J Biol Chem. 1999;274:10219–10226. doi: 10.1074/jbc.274.15.10219. [DOI] [PubMed] [Google Scholar]
  120. Warburton D., Wuenschell C., Flores-Delgado G., Anderson K. Commitment and differentiation of lung cell lineages. Biochem Cell Biol. 1998;76:971–995. doi: 10.1139/bcb-76-6-971. [DOI] [PubMed] [Google Scholar]
  121. Ward S., Muller N.L. Pulmonary complications following lung transplantation. Clin Radiol. 2000;55:332–339. doi: 10.1053/crad.2000.0439. [DOI] [PubMed] [Google Scholar]
  122. Weinacker A.B., Vaszar L.T. Acute respiratory distress syndrome: physiology and new management strategies. Annu Rev Med. 2001;52:221–237. doi: 10.1146/annurev.med.52.1.221. [DOI] [PubMed] [Google Scholar]
  123. Weiss D.J., Strandjord T.P., Liggitt D., Clark J.G. Perflubron enhances adenovirus-mediated gene expression in lungs of transgenic mice with chronic alveolar filling. Hum Gene Ther. 1999;10:2287–2293. doi: 10.1089/10430349950016933. [DOI] [PubMed] [Google Scholar]
  124. Welsh M.J., Smith A.E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73:1251–1254. doi: 10.1016/0092-8674(93)90353-R. [DOI] [PubMed] [Google Scholar]
  125. Worgall S., Leopold P.L., Wolff G., Ferris B., Van Roijen N., Crystal R.G. Role of alveolar macrophages in rapid elimination of adenovirus vectors administered to the epithelial surface of the respiratory tract. Hum Gene Ther. 1997;8:1675–1684. doi: 10.1089/hum.1997.8.14-1675. [DOI] [PubMed] [Google Scholar]
  126. Xing Z., Ohkawara Y., Jordana M., Graham F.L., Gauldie J. Adenoviral vector-mediated interleukin-10 expression in vivo: intramuscular gene transfer inhibits cytokine responses in endotoxemia. Gene Ther. 1997;4:140–149. doi: 10.1038/sj.gt.3300371. [DOI] [PubMed] [Google Scholar]
  127. Yei S., Mittereder N., Tang K., O’Sullivan C., Trapnell B.C. Adenovirusmediated gene transfer for cystic fibrosis: quantitative evaluation of repeated in vivo vector administration to the lung. Gene Ther. 1994;1:192–200. [PubMed] [Google Scholar]
  128. Yen N., Ioannides C.G., Xu K., et al. Cellular and humoral immune responses to adenovirus and p53 protein antigens in patients following intratumoral injection of an adenovirus vector expressing wild-type P53 (Ad-p53) Cancer Gene Ther. 2000;7:530–536. doi: 10.1038/sj.cgt.7700138. [DOI] [PubMed] [Google Scholar]
  129. Yew N.S., Przybylska M., Ziegler R.J., Liu D., Cheng S.H. High and sustained transgene expression in vivo from plasmid vectors containing a hybrid ubiquitin promoter. Mol Ther. 2001;4:75–82. doi: 10.1006/mthe.2001.0415. [DOI] [PubMed] [Google Scholar]
  130. Yew N.S., Wang K.X., Przybylska M., et al. Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes. Hum Gene Ther. 1999;10:223–234. doi: 10.1089/10430349950019011. [DOI] [PubMed] [Google Scholar]
  131. Yew N.S., Zhao H., Wu I.H., et al. Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs. Mol Ther. 2000;1:255–262. doi: 10.1006/mthe.2000.0036. [DOI] [PubMed] [Google Scholar]
  132. Yonemitsu Y., Kitson C., Ferrari S., et al. Efficient gene transfer to airway epithelium using recombinant Sendai virus. Nat Biotechnol. 2000;18:970–973. doi: 10.1038/79463. [DOI] [PubMed] [Google Scholar]
  133. Zabner J., Fasbender A.J., Moninger T., Poellinger K.A., Welsh M.J. Cellular and molecular barriers to gene transfer by a cationic lipid. J Biol Chem. 1995;270:18997–19007. doi: 10.1074/jbc.270.32.18997. [DOI] [PubMed] [Google Scholar]
  134. Zavorotinskaya T., Tomkinson A., Murphy J.E. Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13. Mol Ther. 2003;7:155–162. doi: 10.1016/S1525-0016(02)00050-3. [DOI] [PubMed] [Google Scholar]
  135. Zhan Y., Jiang Q., Dudus L., Yankaskas J.R., Engelhardt J.F. Vector-specific profiles of two independent primary defects in cystic fibrosis airways. Hum Gene Ther. 1998;20:635–648. doi: 10.1089/hum.1998.9.5-635. [DOI] [PubMed] [Google Scholar]
  136. Zhu N., Liggitt D., Liu Y., Debs R. Systemic gene expression after intravenous DNA delivery into adult mice. Science. 1993;261:209–211. doi: 10.1126/science.7687073. [DOI] [PubMed] [Google Scholar]
  137. Ziady A.G., Kelley T.J., Milliken E., Ferkol T., Davis P.B. 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. doi: 10.1006/mthe.2002.0556. [DOI] [PubMed] [Google Scholar]
  138. Ziesche R., Hofbauer E., Wittmann K., Petkov V., Block L.H. A preliminary study of long-term treatment with interferon gamma-1β and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 1999;341:1264–1269. doi: 10.1056/NEJM199910213411703. [DOI] [PubMed] [Google Scholar]
  139. 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 regulator gene to a lung segment of individuals with cystic fibrosis. Hum Gene Ther. 1999;10:2973–2985. doi: 10.1089/10430349950016384. [DOI] [PubMed] [Google Scholar]

Articles from Principles of Molecular Medicine are provided here courtesy of Nature Publishing Group

RESOURCES