The Status of Gene Therapy for Cystic Fibrosis

Daniel J. Weiss; Joseph M. Pilewski

doi:10.1055/s-2004-815670

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2003; 24(6): 749-770
DOI: 10.1055/s-2004-815670

The Status of Gene Therapy for Cystic Fibrosis

Daniel J. Weiss¹ , Joseph M. Pilewski^2,3,4

¹Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont
²Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
³Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
⁴Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Abstract

ABSTRACT

Cystic fibrosis (CF) has been a primary focus for gene therapy of lung diseases because the genetic cause is known and the airway epithelium is accessible for direct deoxyribonucleic acid (DNA) delivery. Soon after the mutated gene was identified in 1989, investigators demonstrated that transfer of a normal copy of the CF gene corrected ion transport abnormalities, thus validating the potential for use of gene therapy for this autosomal recessive disease. However, subsequent studies in a variety of in vitro and animal models, and more limited human studies, have revealed several obstacles to gene therapy for CF: (1) The incomplete understanding of CF lung disease pathogenesis, particularly the relative importance of ion transport and other cellular abnormalities (including glycoconjugate processing, pH regulation of intracellular organelles, and membrane trafficking), and of surface epithelial versus submucosal gland CF transmembrane regulator (CFTR) expression, generates uncertainty as to the necessary target cells for gene transfer and the optimum end point(s) for short-term human studies. (2) The airway epithelium has protective barriers against viral infection that impair gene transfer with several vectors, including recombinant viruses and DNA conjugates. Improvement in DNA transfer technology will be necessary for successful gene therapy. (3) Immune responses to recombinant viruses and inflammatory effects of bacterial DNA are only partially understood and appear to limit efficacy, particularly with repeated administration. Identification of these obstacles is prerequisite for progress, and recent studies with novel DNA delivery methods appear promising.

KEYWORDS

Gene therapy - cystic fibrosis - airway epithelium - adenovirus - adeno-

Full Text

References

REFERENCES

1 Riordan J R, Rommens J M, Kerem B S. et al . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science . 1989; 245 1066-1073
2 Rommens J M, Iannuzzxi M C, Kerem B S. et al . Identification of the cystic fibrosis gene: chromosome walking and jumping. Science . 1989; 245 1059-1065
3 Collins F S. Cystic fibrosis: molecular biology and therapeutic implications. Science . 1992; 256 774-779
4 Welsh M J, Smith A E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell . 1993; 73 1251-1254
5 Mulligan R C. The basic science of gene therapy. Science . 1993; 260 926-932
6 Pilewski J M, Frizzell R A. Role of CFTR in airway disease. Physiol Rev . 1999; 79 (suppl 1) S215-S255
7 Wine J J. The genesis of cystic fibrosis lung disease. J Clin Invest . 1999; 103 309-312
8 Rich D P, Anderson M P, Gregory R J. et al . Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature . 1990; 347 358-363
9 Sheppard D N, Welsh M J. Structure and function of the CFTR chloride channel. Physiol Rev . 1999; 79 S23-S45
10 Schwiebert E M, Benos D J, Egan M E, Stutts M J, Guggino W B. CFTR is a conductance regulator as well as a chloride channel. Physiol Rev . 1999; 79 S145-S166
11 Kunzelmann K. Mechanisms of the inhibition of epithelial Na(+) channels by CFTR and purinergic stimulation. Kidney Int . 2001; 60 455-461
12 Boucher R C. Airway epithelial fluid transport. Am Rev Respir Dis . 1994; 150 271-593
13 Cheng P W, Boat T F, Cranfill K, Yankaskas J R, Boucher R C. Increased sulfation of glycoconjugates by cultured nasal epithelial cells from patients with cystic fibrosis. J Clin Invest . 1989; 84 68-72
14 Imundo L, Barasch J, Prince A, Al-Awqati Q. Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci USA . 1995; 92 3019-3023
15 Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, Al-Awqati Q. Acidification of intracellular organelles is defective in cystic fibrosis. Nature . 1992; 352 70-73
16 Poschet J F, Boucher J C, Tatterson L, Skidmore J, Van Dyke W R, Deretic V. Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung. Proc Natl Acad Sci USA . 2001; 98 13972-13977
17 Coakley R D, Boucher R C. Regulation and functional significance of airway surface liquid pH. JOP Journal of Pancreas . 2001; 2 (suppl 4) S294-S300
18 Bradbury N A, Jilling T, Berta G, Sorscher E J, Bridges R J, Kirk K L. Regulation of plasma membrane recycling by CFTR. Science . 1992; 256 530-532
19 Bradbury N A. Intracellular CFTR: localization and function. Physiol Rev . 1999; 79 S175-S191
20 Lloyd Mills M C, Pereira M C, Dormer R L, McPherson M A. An antibody against a CFTR derived synthetic peptide inhibits beta-adrenergic stimulation of mucin secretion. Biochem Biophys Res Commun . 1992; 188 1146-1152
21 Gao L, Kim K J, Yankaskas J R, Forman H J. Abnormal glutathione transport in cystic fibrosis airway epithelia. Am J Physiol . 1999; 277 L113-L118
22 Matsui H, Grubb B R, Tarran R. et al . Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell . 1998; 95 1005-1015
23 Trapnell B C, Chu C S, Paako P K. et al . Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc Natl Acad Sci USA . 1991; 88 6565-6569
24 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
25 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
26 Jacquot J, Puchelle E, Hinnrasky J. et al . Localization of the cystic fibrosis transmembrane conductance regulator in airway secretory glands. Eur Respir J . 1993; 6 169-176
27 Knowles M R, Boucher R C. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest . 2002; 109 571-577
28 Drumm M L. Pope HA, Cliff WH, et al. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell . 1990; 62 1227-1233
29 Rich D P, Anderson M P, Gregory R J. et al . Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature . 1990; 347 358-363
30 Oceandy D, McMorran B J, Smith S N. et al . Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities. Hum Mol Genet . 2002; 11 1059-1067
31 Johnson L G, Olsen J C, Sarkadi B, Moore K L, Swanstrom R, Boucher R C. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nat Genet . 1992; 2 21-25
32 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
33 Ramalho A S, Beck S, Meyer M, Penque D, Cutting G R, Amaral M D. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am J Respir Cell Mol Biol . 2002; 27 619-627
34 Pickles R J, McCarty D, Matsui H, Hart P J, Randell S H, Boucher R C. Limited entry of adenovirus vectors into well-differentiated airway epithelium is responsible for inefficient gene transfer. J Virol . 1998; 72 6014-6023
35 Walters R W, Grunst T, Bergelson J M, Finberg R W, Wlesh 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
36 Wang G, Zabner J, Deering C. et al . Increasing epithelial junction permeability enhances gene transfer to mouse tracheal epithelium in vivo. Am J Respir Cell Mol Biol . 2000; 22 129-138
37 Chu Q, St George A J, Lukason M, Cheng S H, Scheule R K, Eastman S J. EGTA enhancement of adenovirus-mediated gene transfer to mouse tracheal epithelium in vivo. Hum Gene Ther . 2001; 12 455-467
38 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
39 Pilewski J M, Latoche J D, Arcasoy S M, Albelda S M. Expression in integrin cell adhesion receptors during human airway epithelial repair in vivo. Am J Physiol . 1997; 273 L256-L263
40 Kitson C, Angel B, Judd D. et al . The extra-and intercellular barriers to lipid and adenovirus-mediated pulmonary gene transfer to native sheep airway epithelium. Gene Ther . 1998; 6 534-546
41 Perricone M A, Rees D D, Sacks C R, Smith K A, Kaplan J M, St George A J. Inhibitory effect of cystic fibrosis sputum on adenovirus-mediated gene transfer in cultured epithelial cells. Hum Gene Ther . 2000; 11 1997-2008
42 Haddad I Y, Sorscher E J, Garver J I, Hong J, Tzeng E, Matalon S. Modulation of adenovirus-mediated gene transfer by nitric oxide. Am J Respir Cell Mol Biol . 1997; 16 501-509
43 van Heeckeren A, Ferkol T, Tosi M. Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice. Gene Ther . 1998; 5 345-351
44 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
45 Otake K, Ennist D L, Harrod K, Trapnell B C. Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses. Hum Gene Ther . 1998; 9 2207-2222
46 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
47 Worgall S, Wolff G, Falck-Pedersen E, Crystal R G. Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum Gene Ther . 1997; 8 37-44
48 Bromberg J S, Debruyne L A, Qin L. Interactions between the immune system and gene therapy vectors: Bidirectional regulation of response and expression. Adv Immunol . 1998; 69 353-409
49 Look D C, Brody S L. Engineering viral vectors to subvert the airway defense response. Am J Respir Cell Mol Biol . 1999; 20 1103-1106
50 Morral N, O'Neial W, Zhou H, Langston C, Beaudet A. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors. Hum Gene Ther . 1997; 8 1275-1286
51 Song W, Kong H L, Traktman P, Crystal R G. Cytotoxic T lymphocyte responses to proteins encoded by heterologous transgenes transferred in vivo by adenoviral vectors. Hum Gene Ther . 1997; 8 1207-1217
52 Yang Y, Jooss K U, Su Q, Ertl H C, Wilson J M. Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther . 1996; 3 137-144
53 Whitsett J A, Dey C R, Stripp B R. et al . Human cystic fibrosis transmembrane conductance regulator directed to respiratory epithelial cells of transgenic mice. Nat Genet . 1992; 2 13-20
54 Kaplan J M, Smith A E. Transient immunosuppression with deoxyspergualin improves longevity of transgene expression and ability to readminister adenoviral vector to the mouse lung. Hum Gene Ther . 1997; 8 1095-1104
55 Kaplan J, St George A J, Pennington S E. et al . Humoral and cellular immune responses of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2. Gene Ther . 1996; 3 117-127
56 Thorne P S, McCray P B, Howe T S, O'Neill M A. Early-onset inflammatory responses in vivo to adenoviral vectors in the presence or absence of lipopolysaccharaide-induced inflammation. Am J Respir Cell Mol Biol . 1999; 20 1155-1164
57 Weiss D J, Bonneau L, Liggitt D. Use of perfluorochemical liquid allows earlier detection and use of less adenovirus vector for gene expression in normal lung and enhances gene expression in acutely injured lung. Molecular Therapy . 2001; 3 734-745
58 Suzuki M, Suzuki S, Yamamoto N. et al . Immune responses against replication-deficient adenovirus inhibit ovalbumin-specific allergic reactions in mice. Hum Gene Ther . 2000; 11 827-838
59 Morsy M A, Gu M C, Motzel S. et al . An Adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Appl Biol Sci . 1998; 95 7866-7871
60 Morral N, Parks R J, Zhou H. et al . High doses of a helper-dependent adenoviral vector yield supraphysiological levels of α₁-antitrypsin with negligible toxicity. Hum Gene Ther . 1998; 9 2709-2716
61 Chillón M, Lee J H, Fasbender A, Welsh M J. Adenovirus complexed with polyethylene glycol and cationic lipid is shielded from neutralizing antibodies in vitro. Gene Ther . 1998; 5 995-1002
62 O'Riordan C R, Lachapell A, Delgado C. et al . PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther . 1999; 10 1349-1358
63 Croyle M A, Chirmule N, Zhang Y, Wilson J M. “Stealth” adenoviruses 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
64 White G C, Roberts H R. Gene therapy for hemophilia: a step closer to reality. Mol Ther . 2000; 1 207-208
65 Green E S, Rendahl K G, Zhou S. et al . Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18. Mol Ther . 2001; 3 507-515
66 Conrad C K, Allen S S, Afione S A. et al . Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther . 1996; 3 658-668
67 Flotte T R, Solow R, Owens R A, Afione S A, Zeitlin P L, Carter B J. Gene expression from adeno-associated virus vectors in airway epithelial cells. Am J Respir Cell Mol Biol . 1992; 7 349-356
68 Flotte T R, Carter B J. Adeno-associated virus vectors for gene therapy. Gene Ther . 1995; 2 357-362
69 Halbert C L, Alexander I E, Wolgamot G M, Miller A D. Adeno-associated virus vectors transduce primary cells much less efficiently than immortalized cells. J Virol . 1995; 69 1473-1479
70 Duan D, Yue Y, Yan Z, McCray P BJ, Engelhardt J F. Polarity influences the efficiency of recombinant adenoassociated virus infection in differentiated airway epithelia. Hum Gene Ther . 1998; 9 2761-2776
71 Teramoto S, Bartlett J S, McCarty D, Xiao X, Samulski R J, Boucher R C. Factors influencing adeno-associated virus-mediated gene transfer to human cystic fibrosis airway epithelial cells: comparison with adenovirus vectors. J Virol . 1998; 72 8904-8912
72 Bals R, Xiao W, Sang N, Weiner D J, Meegalla R L, Wilson J M. Transduction of well-differentiated airway epithelium by recombinant adeno-associated virus is limited by vector entry. J Virol . 1999; 73 6085-6088
73 Summerford C, Samulski R J. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol . 1998; 72 1438-1445
74 Qing K, Mah C, Hansen J, Zhou S, Dwarki V, Srivastava A. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med . 1999; 5 71-77
75 Summerford C, Bartlett J S, Samulski R J. AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med . 1999; 5 78-82
76 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
77 Yan Z, Zak R, Luxton G W, Ritchie T C, Bantel-Schaal U, Engelhardt J F. 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
78 Sanlioglu S, Engelhardt J F. Cellular redox state alters recombinate adeno-associated virus transduction through tyrosine phosphatase pathways. Gene Ther . 1991; 6 1427-1437
79 Sanlioglu S, Benson P K, Yang J, Atkinson E M, Reynolds T, Engelhardt J F. Endocytosis and nuclear trafficking of adeno-associated virus type 2 are controlled by rac1 and phosphatidylinositol-3 kinase activation. J Virol . 2000; 74 9184-9196
80 Qing K, Hansen J, Weigel-Kelley K A, Tan M, Zhou S, Srivastava A. Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression. J Virol . 2001; 75 8968-8976
81 Halbert C L, Allen J M, Miller A D. Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene. Nat Biotechnol . 2002; 20 697-701
82 Ostedgaard L S, Zabner J, Vermeer D W. 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
83 Aitken M L, Moss R B, Waltz D A. et al . A phase 1 study of aerosolized administration of tgAAVCF to cystic fibrosis patients with mild lung disease. Hum Gene Ther . 2001; 12 1907-1916
84 Chao H, Liu Y, Rabinowitz J, Li C, Samulski R J, Walsh C E. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther . 2000; 2 619-623
85 Walters R, Yi S M, Keshavjee S. 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 20606-20610
86 Kaludov N, Brown K E, Walters R W, Zabner J, Chiorini J A. Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J Virol . 2001; 75 6884-6893
87 Halbert C L, Allen J M, Miller A D. Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J Virol . 2001; 75 6615-6624
88 Walters R W, Yi S M, Keshavjee S. et al . Binding of adeon-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. J Biol Chem . 2001; 276 20610-20616
89 Virella-Lowell I, Poirier A, Chesnut K A, Brantlyn M, Flotte T R. Inhibition of recombinant adeno-associated virus (rAAV) transduction by bronchial secretions from cystic fibrosis patients. Gene Ther . 2000; 7 1783-1789
90 McCray P B, Wang G, Kline J N. et al . Alveolar macrophages inhibit retrovirus-mediated gene transfer to airway epithelia. Hum Gene Ther . 1997; 8 1087-1093
91 Wang G, Davidson B L, Melchert P. et al . Influence of cell polarity on retrovirus-mediated gene transfer to differentiated human airway epithelial epithelia. J Virol . 1998; 72 9818-9826
92 Engelhardt J F, Yankaskas J R, Wilson J M. In vivo retroviral gene transfer into human bronchial epithelia of xenografts. J Clin Invest . 1992; 90 2598-2607
93 Halbert C L, Aitken M L, Miller A D. Retroviral vectors efficiently transduce basal and secretory airway epithelial cells in vitro resulting in persistent gene expression in organotypic culture. Hum Gene Ther . 1996; 7 1871-1881
94 Pitt B R, Schwarz M A, Pilewski J M. et al . Retrovirus-mediated gene transfer in lungs of living fetal sheep. Gene Ther . 1995; 2 344-350
95 Wang G, Davidson B L, Melchert P. et al . Influence of cell polarity on retrovirus-mediated gene transfer to differentiated human airway epithelial epithelia. J Virol . 1998; 72 9818-9826
96 Johnson L G, Mewshaw J P, Ni H, Friedman T, Boucher R C, Olsen J C. Effect of host modification and age on airway epithelial gene transfer mediated by a murine leukemia virus-derived vector. J Virol . 1998; 72 8861-8872
97 Goldman M J, Lee P S, Yang J S, Wilson J M. Lentiviral vectors for gene therapy of cystic fibrosis. Hum Gene Ther . 1997; 8 2261-2268
98 Lever A M. Lentivral vectors: progress and potential. Curr Opin Mol Ther . 2000; 2 488-496
99 Wang G, Sinn P L, McCray Jr B P. Development of retroviral vectors for gene transfer to airway epithelia. Curr Opin Mol Ther . 2000; 2 497-506
100 Hacein-Bey-Abina S, von Kalle C, Schmidt M. et al . A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med . 2003; 348 255-256
101 Zhang L, Peeples M E, Boucher R C, Collins P L, Pickles R J. Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology. J Virol . 2003; 76 5654-5666
102 Yonemitsu Y, Kitson C, Ferrari S. et al . Efficient gene transfer to airway epithelium using recombinant Sendai virus. Nat Biotechnol . 2000; 18 970-973
103 Slepushkin V A, Staber P D, Wang G, McCray Jr B P, Davidson B L. Infection of human airway epithelia with H1N1, H2N2, and H3N2 Influenza A virus strains. Mol Ther . 2001; 3 395-402
104 Scheule R K, St George A J, Bagley R G. et al . Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung. Hum Gene Ther . 1997; 8 689-707
105 Tan Y, Liu F, Li Z, Li S, Huang L. Sequential injection of cationic liposome and plasmid DNA effectively transfects the lung with minimal inflammatory toxicity. Mol Ther . 2001; 3 673-682
106 Ruiz F E, Clancy J P, Perricone M A. et al . A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum GeneTher . 2001; 12 751-761
107 Freimark B D, Blezinger H P, Florack V J. et al . Cationic lipids enhance cytokine and cell influx levels in the lung folloiwng administration of plasmid: cationic lipid complexes. J Immunol . 1998; 160 4580-4586
108 Li S, Wu S P, Whitmore M. et al . Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am J Physiol . 1999; 276 L796-L804
109 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
110 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
111 Krieg A M. Minding the Cs and Gs. Mol Ther . 2000; 1 209-210
112 Tsan M F, White J E, Shepard B. Lung-specific direct in vivo gene transfer with recombinant plasmid DNA. Am J Physiol . 1995; 268 L1052-L1056
113 Tsan M F, White J E, Pastore J N, Hayes V D, Shepard B A, Lee C Y. Pulmonary response to plasmid DNA and immunohistochemical localization of transgene expression. Exp Lung Res . 1996; 22 651-666
114 Kukowska-Latallo J F, Raczka E, Quintana A, Chen C, Rymaszewski M, Baker J R. Intravascular and endobronchial DNA delivery to muring lung tissue using a novel, nonviral vector. Hum Gene Ther . 2000; 11 1385-1395
115 Raczka E, Kukowska-Latallo J F, Rymaszewski M, Chen C, Baker J R. The effect of synthetic surfactant Exosurf on gene transfer in mouse lung in vivo. Gene Ther . 1998; 5 1333-1339
116 Yew N S, Wysokenski D M, Wang K X. et al . Optimization of plasmid vectors for high-level expression in lung epithelial cells. Hum Gene Ther . 1997; 8 575-584
117 Fasbender A J, Zabner J, Welsh M J. Optimization of cationic lipid-mediated gene transfer to airway epithelia. Am J Physiol . 1995; 269 L45-L51
118 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
119 Debs R, Pian M, Gaensler K, Clements J, Friend D S, Dobbs L. Prolonged transgene expression in rodent lung cells. Am J Respir Cell Mol Biol . 1992; 7 406-413
120 Matsui H, Johnson L G, Randell S H, Boucher R C. Loss of binding and entry of liposome-DNA complexes decreases transfection efficiency in differentiated airway epithelial cells. J Biol Chem . 1997; 272 1117-1126
121 Stribling R, Brunette E, Liggitt D, Gaensler K, Debs R. Aerosol gene delivery in vivo. 1995. Proc Natl Acad Sci USA . 1992; 89 11277-11281
122 Nilsson S K, Dooner M S, Weier H U. et al . Cells capable of bone production engraft from whole bone marrow transplants in nonablated mice. J Exp Med . 1999; 189 729-734
123 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
124 Fasbender A, Zabner J, Zeiher B G, Welsh M J. A low rate of cell proliferation and reduced DNA uptake limit cationic lipid-mediated gene transfer to primary cultures of ciliated human airway epithelia. Gene Ther . 1997; 4 1173-1180
125 Tsan M F, Tsan G L, White J E. Surfactant inhibits cationic liposome-mediated gene transfer. Hum Gene Ther . 1997; 8 817-825
126 Duncan J D, Whitsett J A, Horowitz A D. Pulmonary surfactant inhibits cationic liposome-mediated gene delivery to respiratory epithelial cells in vitro. Hum Gene Ther . 1997; 8 431-438
127 Ernst U, Ulrichskotter S, Schmalix W A. et al . Interaction of liposomal and polycationic transfection complexes with pulmonary surfactant. J Gene Med . 1999; 1 331-340
128 Stern M, Caplen N J, Browning J E. et al . The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro. Gene Ther . 1998; 5 91-98
129 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
130 Harris C E, Agarwal S, Hu P, Wagner E, Curiel D T. Receptor-mediated gene transfer to airway epithelial cells in primary culture. Am J Respir Cell Mol Biol . 1993; 9 441-447
131 Gao L, Wagner E, Cotten M. et al . Direct in vivo gene transfer to airway epithelium employing adenovirus-polylysine-DNA complexes. Hum Gene Ther . 1993; 4 17-24
132 Fajac I, Briand P, Monsigny M, Midoux P. Sugar-mediated uptake of glycosylated polylysines and gene transfer into normal and cystic fibrosis airway epithelial cells. Hum Gene Ther . 1999; 10 395-406
133 Kukowska-Latallo J F, Raczka E, Quintana A, Chen C, Rymaszewski M, Baker Jr R J. Intravascular and endobronchial DNA delivery to murine lung tissue using a novel, nonviral vector. Hum Gene Ther . 2000; 11 1385-1395
134 Schughart K, Bischoff R, Rasmussen U B. et al . Solvoplex: a new type of synthetic vector for intrapulmonary gene delivery. Hum Gene Ther . 1999; 10 2891-2905
135 Ferkol T, Perales J C, Eckman E, Kaetzel C S, Hanson R W, Davis P B. Gene transfer into the airway epithelium of animals by targeting the polymeric immunoglobulin receptor. J Clin Invest . 1995; 95 493-502
136 Gupta S, Eastman J, Silski C, Ferkol T, Davis P B. Single chain Fv: a ligand in receptor-mediated gene delivery. Gene Ther . 2001; 8 586-592
137 Ziady A G, Kelley T J, Milliken E, Ferkol T, Davis P B. Functional evidence of CFTR gene transfer in nasal epithelial of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme comlex receptor. Mol Ther . 2002; 5 413-419
138 Kollen W J, Schembri F M, Gerwig G J, Vliegenthart J F, Glick M C, Scanlin T F. Enhanced efficiency of lactosylated poly-L-lysine-mediated gene transfer into cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol . 1999; 20 1081-1086
139 Gautam A, Densmore C L, Golunski E, Xu B, Waldrep J C. Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes. Mol Ther . 2001; 3 551-556
140 Gautam A, Densmore C L, Xu B, Waldrep J C. Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery. Mol Ther . 2000; 2 63-70
141 Gautam A, Densmore C L, Waldrep J C. Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes. Gene Ther . 2000; 2 318-323
142 Gautam A, Densmore C L, Waldrep J C. Pulmonary cytokine responses associated with PEI-DNA aerosol gene therapy. Gene Ther . 2001; 8 254-257
143 Pilewski J M. Gene therapy for airway diseases: continued progress towards identifying and overcoming barriers to efficiency. Am J Respir Cell Mol Biol . 2002; 27 117-121
144 Weiss D J. Delivery of gene transfer vectors to lung: obstacles and the role of adjunct techniques for airway administration. Mol Ther . 2002; 6 148-152
145 Look D C, Brody S L. Engineering viral vectors to subvert the airway defense response. Am J Respir Cell Mol Biol . 1999; 20 1103-1106
146 Bromberg J S, Debruyne L A, Qin L. Interactions between the immune system and gene therapy vectors: bidirectional regulation of response and expression. Adv Immunol . 1998; 69 353-409
147 Halbert C L, Standaert T A, Wilson C B, Miller A D. Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J Virol . 1998; 72 9795-9805
148 Zabner J, Ramsey B W, Meeker D P. et al . Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J Clin Invest . 1996; 97 1504-1511
149 Engelhardt J F, Simon R H, Yang Y. et al . Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: biological efficacy study. Hum Gene Ther . 1993; 4 759-769
150 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 2973-2985
151 Cipolla D C, Gonda I, Shak S, Kovesdi I, Crystal R, Sweeney T D. Coarse spray delivery to a localized region of the pulmonary airways for gene therapy. Hum Gene Ther . 2000; 11 361-371
152 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 1165-1166
153 Beck S E, Laube B L, Barberena C I. et al . Deposition and expression of aerosolized rAAV vectors in the lungs of rhesus macaques. Mol Ther . 2002; 6 546-554
154 McDonald R J, Lukason M J, Raabe O G. et al . Safety of airway gene transfer with Ad2/CFTR2: aerosol administration in the nonhuman primate. Hum Gene Ther . 1997; 8 411-422
155 Katkin J P, Gilbert B E, Langston C, French K, Beaudet A L. Aerosol delivery of a β-galactosidase adenoviral vector to the lungs of rodents. Hum Gene Ther . 1995; 6 985-995
156 Sene C, Bout A, Imler J L. et al . Aerosol-mediated delivery of recombinant adenovirus to the airways of nonhuman primates. Hum Gene Ther . 1995; 6 1587-1593
157 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
158 Eastman S J, Tousignant J D, Lukason M J, Chu Q, Cheng S H, Scheule R K. Aerosolization of cationic lipid:pDNA complexes in vitro optimization of nebulizer parameters for human clinical studies. Hum Gene Ther . 1998; 9 43-52
159 Brown A R, Chowdhury S I. Propellant-driven aerosols of DNA plasmids for gene expression. J Aerosol Med . 1997; 10 129-146
160 Stern M, Sorgi F, Hughes C. et al . The effects of jet nebulisation on cationic liposome-mediated gene transfer in vitro. Gene Ther . 1998; 5 583-593
161 Crook K, McLachlan G, Stevenson B J, Porteous D J. Plasmid DNA molecules complexed with cationic liposomes are protected from degradation by nucleases and shearing by aerosolization. Gene Ther . 1996; 3 834-839
162 Muir D FC. Particle Deposition: The Lung: Scientific Foundations, 1839-1843. New York: Raven Press Ltd; 1991
163 Walters R W, van't Hof W, Yi S M. et al . Apical localization of the coxsackie-adenovirus receptor by glycosyl-phosphatidylinositol modification is sufficient for adenovirus-mediated gene transfer through the apical surface of human airway epithelia. J Virol . 2001; 75 7703-7711
164 Zhang H G, Zhou T, Yang P, Edwards C KI, Curiel D T, Mountz J D. Inhibition of tumor necrosis factor α decreases inflammation and prolongs adenovirus gene expression in lung and liver. Hum Gene Ther . 1998; 9 1875-1884
165 Bastian A, Bewig B. Inhibition of adenovirus-mediated gene transfer by bronchoalveolar lavage fluid. Gene Ther . 1999; 6 637-642
166 Bastian A, Schafer H. Human alpha-defensin 1 (HNP-1) inhibits adenoviral infection in vitro. Regul Pept . 2001; 101 157-161
167 Jobe A H, Ueda T, Whitsett J A, Trapnell B C, Ikegami M. Surfactant enhances adenovirus-mediated gene expression in rabbit lungs. Gene Ther . 1996; 3 775-779
168 Katkin J P, Husser R C, Langston C, Welty S E. Exogenous surfactant enhances the delivery of recombinant adenoviral vectors to the lung. Hum Gene Ther . 1997; 8 171-176
169 Arcasoy S M, Latoche J, Gondor M. et al . MUC1 and other sialoglycoconjugates inhibit adenovirus-mediated gene transfer. Am J Respir Cell Mol Biol . 1997; 17 422-435
170 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
171 Yang Y, Greenough K, Wilson J M. Transient immune blockade prevents formation of neutralizing antibody to recombinant adenovirus and allows repeated gene transfer to mouse liver. Gene Ther . 1996; 3 412-420
172 Halbert C L, Standaert T A, Aitken M L, Alexander I E, Russell D W, Miller A D. Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration. J Virol . 1997; 71 5932-5941
173 Yang Y, Trinchieri G, Wilson J M. Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung. Nat Med . 1995; 1 890-893
174 Yang Y, Li Q, Ertl H C, Wilson J M. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol . 1995; 69 2004-2015
175 Lei D, Lehmann M, Shellito J E. et al . Nondepleting anti-CD4 antibody treatment prolongs lung-directed E1-deleted adenovirus-mediated gene expression in rats. Hum Gene Ther . 1996; 7 2273-2279
176 Scaria A, St George A J, Gregory R J. et al . Antibody to CD40 ligand inhibits both humoral and cellular immune responses to adenoviral vectors and facilitates repeated administration to mouse airway. Gene Ther . 1997; 4 611-617
177 Shean M K, Baskin G, Sullivan D. et al . Immunomodulation and adenoviral-mediated gene transfer to the lungs of non-human primates. Hum Gene Ther . 2000; 11 1047-1055
178 Rahman A, Tsai V, Goudreau A. et al . Specific depletion of human anti-adenovirus antibodies facilitates transduction in an in vivo model for systemic gene therapy. Mol Ther . 2001; 3 768-778
178a Scott E S, Wiseman J W, Evans M J, Colledge W H. Enhanced gene delivery to human airway epithelial cells using an integrin-targeting lipoplex. J Gene Med . 2001; 3 125-134
178b Drapkin P T, O'Riordan C R, Yi S M. et al . Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia. J Clin Invest . 2000; 105 589-596
179 Kreda S M, Pickles R J, Lazarowski E R, Boucher R C. G-protein-coupled receptors as targets for gene transfer vectors using natural small-molecule ligands. Nat Biotechnol . 2000; 18 635-640
180 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
181 Sakhuja K, Reddy P S, Ganesh S. et al . Optimization of the generation and propagation of gutless adenoviral vectors. Hum Gene Ther . 2003; 14 243-254
182 Lee J H, Zabner J, Welsh M J. Delivery of an adenovirus vector in a calcium phosphate coprecipitate enhances the therapeutic index of gene transfer to airway epithilia. Hum Gene Ther . 1999; 10 603-613
183 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
184 Walters R W, Duan D, Engelhardt J, Welsh M J. Incorporation of adeno-associated virus in a calcium phosphate coprecipitate improves gene transfer to airway epithelia in vitro and in vivo. J Virol . 2000; 74 535-540
185 Arcasoy S M, Latoche J D, Gondor M, Pitt B R, Pilewski J M. Polycations increase the efficiency of adenovirus-mediated gene transfer to epithelial and endothelial cells in vitro. Gene Ther . 1997; 4 32-38
186 Coyne C B, Kelly M M, Boucher R C, Johnson L G. Enhanced epithelial gene transfer by modulation of tight junctions with sodium caprate. Am J Respir Cell Mol Biol . 2000; 23 602-609
187 Gregory L G, Harbottle R P, Lawrence L, Knapton H J, Themis M, Coutelle C. Enhancement of adenovirus-mediated gene transfer to the airways by DEAE dextran and sodium caprate in vivo. Mol Ther . 2003; 7 19-26
188 Zabner J, Zeiher B G, Friedman E, Welsh M J. Adenovirus-mediated gene transfer to ciliated airway epithelia requires pronlonged incubation time. J Virol . 1996; 70 6994-7003
189 Jiang C, Akita G Y, Colledge W H. et al . Increased contact time improves adenovirus-mediated CFTR gene transfer to nasal epithelium of CF mice. Hum Gene Ther . 1997; 8 671-680
190 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 Repir Cell Mol Biol . 2002; 27 133-140
191 Greenough A. Expanded use of surfactant replacement therapy. Eur J Pediatr . 2001; 159 635-640
192 Factor P, Saldias F, Ridge K. et al . Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na, K-ATPase betal subunity gene. J Clin Invest . 1998; 102 1421-1430
193 Factor P, Mendez M, Mutlu G M, Dumasius V. Acute hyperoxic lung injury does not impede adenoviral-mediated alveolar gene transfer. Am J Respir Crit Care Med . 2002; 165 521-526
194 Shaffer T H, Wolfson M R, Clark L C. Liquid ventilation. Pediatr Pulmonol . 1992; 14 102-109
195 Leach C L, Greenspan J S, Rubenstein S D. et al . Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome. N Engl J Med . 1996; 335 761-767
196 Hirschl R B, Conrad S, Kaiser R. et al . Partial liquid ventilation in adult patients with ARDS: a multicenter phase I-II trial. Adult PLV Study Group. Ann Surg . 1998; 228 692-700
197 Papo M C, Paczan P R, Fuhrman B P. et al . Perfluorocarbon-associated gas exchange improves oxygenation, lung mechanics, and survival in a model of adult respiratory distress syndrome. Crit Care Med . 1996; 24 466-474
198 Colton D M, Till G O, Johnson K J, Dean S B, Bartlett R H, Hirschl R B. Neutrophil accumulation is reduced during partial liquid ventilation. Crit Care Med . 1998; 26 1716-1724
199 Croce M A, Fabian T C, Patton J H, Melton S M, Moore M, Trenthem L L. Partial liquid ventilation decreases the inflammatory response in the alveolar environment of trauma patients. J Trauma . 1998; 45 273-282
200 Lisby D A, Ballard P L, Fox W W, Wolfson M R, Shaffer T H, Gonzales L W. Enhanced Distribution of Adenovirus-Mediated Gene Transfer to Lung Parenchyma by Perfluorochemical Liquid Hum Gene Ther . 1997; 8 919-928
201 Weiss D J, Strandjord T P, Jackson J C, Clark J G, Liggitt D. Perfluorochemical liquid-enhanced adenoviral vector distribution and expression in lungs of spontaneously breathing rodents. Exp Lung Res . 1999; 25 317-333
202 Weiss D J, Bonneau L, Allen J M, Miller A D, Halbert C L. Perfluorochemical liquid enhances adeno-associated virus-mediated transgene expression in lung. Mol Ther . 2000; 2 624-630
203 Weiss D J, Baskin G B, Shean M K, Blanchard J L, Kolls J K. Use of perflubron to enhance lung gene expression: safety and initial efficacy studies in non-human primates. Mol Ther . 2002; 5 8-15
204 Weiss D J, Niven R W, Strandjord T P, Liggitt D, Clark J G. Perfluorochemical liquid-enhanced liposomal-mediated gene transfer to lungs of spontaneously breathing rats. Pediatr Pulmonol . 1998; 17 269
205 Lerondel S, Le Pape A, Sene C. et al . Radioisotopic imaging allows optimization of adenovirus lung deposition for cystic fibrosis gene therapy. Hum Gene Ther . 2001; 12 1-11
206 Weiss D J, Strandjord T P, Liggitt D, Clark J G. Perflubron enhances adenoviral-mediated gene expression in lungs of transgenic mice with chronic alveolar filling. Hum Gene Ther . 1999; 10 2287-2293
207 Bonneau L, Shaffer T H, Lukason M, St George J, Wolfson M R. Ingestion in vivo by alveolar macrophages of perflorochemical (PFC) liquid correlates with altered proinflammatory cytokine release. Am J Respir Crit Care Med . 2000; 161 A902
208 Weiss D J, Beckett T, Bonneau L. et al . Transient increase in lung epithelial tight junction permeability: an additional mechanism for enhancement of lung transgene expression by perfluorochemical liquids. Molecular Therapy . 2003; 8 927-935
209 Weiss D J, Bonneau L, Liggitt D. Inhalation of nebulized perflubron enhhances adenovirus mediated gene expression in lung epithelium. Mol Ther . 2003; 5 S68
210 McLean J W, Fox E A, Baluk P. et al . Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice. Am J Physiol (Heart Circ Physiol ) . 1997; 273 H387-H404
211 Huard J, Lochmuller H, Acsadi G, Jani A, Bassie B, Karpati G. The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. Gene Ther . 1995; 2 107-115
212 Rodman D M, San H, Simari R. et al . In vivo gene delivery to the pulmonary circulation in rats: transgene distribution and vascular inflammatory response. Am J Respir Cell Mol Biol . 1997; 16 640-649
213 Zhang Y, Chirmule N, Gao G P. et al . Acute cytokine response to systemic adenovial vectors in mice is mediated by dendritic cells and macrophages. Mol Ther . 2001; 3 697-707
214 Albelda S M, Wiewrodt R, Zuckerman J B. Gene therapy for lung disease: hype or hope?. Ann Intern Med . 2000; 132 649-660
214a Joseph P M, O'Sullivan B P, Lapey A. 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 1369-1382
214b Wagner J A, Nepomuceno I B, Messner A H. et al . A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF used maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther . 2002; 13 1349-1359
214c 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 (AAC-CFTR) in the cystic fibrosis maxillary sinus. Larynogoscope . 1999; 109 266-274
214d Harvey B G, Maroni J, O'Donoghue K A. et al . Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther . 2002; 13 15-63
214e 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
214f 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
214g Hay J G, McElvaney N G, Herena J, Crystal R G. 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 1487-1496
214h Caplen N J, Alton E W, Middelton P G. et al . Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med . 1995; 1 39-46
214i McElvaney N G, Crystal R G. IL-6 release and airway administration of human CFR cDNA adenovirus vector. Nat Med . 1995; 1 182-184
215 Zabner J, Couture L A, Gregory R J, Graham S M, Smith A E, Welsh M J. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell . 1993; 75 207-216
216 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; 333 823-831
217 McElvaney N G, Crystal R G. IL-6 release and airway administration of human CFR cDNA adenovirus vector. Nat Med . 1995; 1 182-184
218 Balter M. Gene therapy on trial. Science . 2000; 288 951-957
219 Flotte T R, Afione S A, Conrad C. et al . Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci USA . 1993; 90 10613-10617
220 Conrad C K, Allen S S, Afione S A. et al . Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther . 1996; 3 658-668
221 Wagner J A, Reynolds T, Moran M L. et al . Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet . 1998; 351 1702-1703
222 Moss R B, Aitken M, Clancy J. et al . A multi-center, double-blind, placebo controlled, phase II study of aerosolized TGAAVCFTR in cystic fibrosis patients with mild lung disease. Pediatr Pulmonol . 2002; S24 A210
223 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
224 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; 1 105-114
225 Zabner J, Cheng S H, Meeker D. et al . Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J Clin Invest . 1997; 100 1529-1537
226 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
227 Reynolds S D, Giangreco A, Power J H, Stripp B R. Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am J Pathol . 2000; 156 269-278
228 Reynolds S D, Hong K U, Giangreco A. et al . Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am J Physiol (Lung Cell Molec Physiol) . 2000; 278 L1256-1263
229 Hong K U, Reynolds S D, Giangreco A, Hurley C M, Stripp B R. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am J Respir Cell Mol Biol . 2001; 24 671-681
230 Giangreco A, Reynolds S D, Stripp B R. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol . 2002; 161 173-182
231 Engelhardt J F, Schlossberg H, Yankaskas J R, Dudus L. Progenitor cells of the adult human airway involved in submucosal gland development. Development . 1995; 121 2031-2046
232 Zepeda M L, Chinoy M R, Wilson J M. Characterization of stem cells in human airway capable of reconstituting a fully differentiated bronchial epithelium. Somat Cell Mol Genet . 1995; 21 61-73
233 Jiang Y, Jahagirdar B N, Reinhardt R L. et al . Pluripotency of mesenchymal stem cells derived from adult marrow. Nature . 2002; 418 41-49
234 Hirschi K K, Goodell M A. Hematopoietic, vascular and cardiac fates of bone marrow-derived stem cells. Gene Ther . 2002; 9 648-652
235 Brazelton T R, Rossi F M, Keshet G I, Blau H M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science . 2000; 290 1775-1779
236 Kotton D N, Ma B Y, Cardoso W V. et al . Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development . 2001; 128 5181-5188
237 Wang X, Montini E, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol . 2002; 161 565-574
238 Wagers A J, Christensen J L, Weissman I L. Cell fate determination from stem cells. Gene Ther . 2002; 9 606-612
239 Krause D S, Theise N D, Collector M I. et al . Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell . 2001; 105 369-377
240 Theise N D, Henegariu O, Grove J. et al . Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol . 2002; 30 1333-1338
241 Grove J E, Lutzko C, Priller J. et al . Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium. Am J Respir Cell Mol Biol . 2002; 27 645-651
242 Bruscia E, Sangiuolo F, Sinibaldi P, Goncz K K, Novelli G, Gruenert D C. CFTR locus by SFHR-mediated targeting. Gene Ther . 2002; 9 683-685
243 Liu X, Jiang Q, Mansfield S G. et al . Partial correction of endogenous DeltaF508 CFTR in human cystic fibrosis airway epithelia by sliceosome-mediated RNA trans-splicing. Nat Biotechnol . 2002; 20 47-52