Gene therapy: light is finally in the tunnel

Abstract

After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber’s congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

Keywords

gene therapy / transgenes / viral vector / non-viral vector / helper-dependent adenoviral vector / adeno-associated virus / lentivirus / cystic fibrosis transmembrane conductance regulator (CFTR) / host immune responses

References

[1] Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M., (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-95 11326284.
[2] Ahmed, R., and Gray, D. (1996). Immunological memory and protective immunity: understanding their relation. Science 272, 54-60 8600537.
[3] Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., Scaramuzza, S., Andolfi, G., Mirolo, M., Brigida, I., (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360, 447-458 19179314.
[4] Aiuti, A., and Roncarolo, M.G. (2009). Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program , 682-689 20008254.
[5] Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., (2002). Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410-2413 12089448.
[6] Alton, E.W., Stern, M., Farley, R., Jaffe, A., Chadwick, S.L., Phillips, J., Davies, J., Smith, S.N., Browning, J., Davies, M.G., (1999). Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 353, 947-954 10459902.
[7] Arcasoy, S.M., Latoche, J., Gondor, M., Watkins, S.C., Henderson, R.A., Hughey, R., Finn, O.J., and Pilewski, J.M. (1997). MUC1 and other sialoglycoconjugates inhibit adenovirus-mediated gene transfer to epithelial cells. Am J Respir Cell Mol Biol 17, 422-435 9376117.
[8] Aronow, B.J., Silbiger, R.N., Dusing, M.R., Stock, J.L., Yager, K.L., Potter, S.S., Hutton, J.J., and Wiginton, D.A. (1992). Functional analysis of the human adenosine deaminase gene thymic regulatory region and its ability to generate position-independent transgene expression. Mol Cell Biol 12, 4170-4185 1508212.
[9] Ashtari, M., Cyckowski, L.L., Monroe, J.F., Marshall, K.A., Chung, D.C., Auricchio, A., Simonelli, F., Leroy, B.P., Maguire, A.M., Shindler, K.S., (2011). The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest 121, 2160-2168 21606598.
[10] Bainbridge, J.W., Smith, A.J., Barker, S.S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G.E., Stockman, A., Tyler, N., (2008). Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358, 2231-2239 18441371.
[11] Baldwin, A.S. Jr. (1996). The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14, 649-683 8717528.
[12] Bals, R., Xiao, W., Sang, N., Weiner, D.J., Meegalla, R.L., and Wilson, J.M. (1999). Transduction of well-differentiated airway epithelium by recombinant adeno-associated virus is limited by vector entry. J Virol 73, 6085-6088 10364362.
[13] Barnett, B.G., Crews, C.J., and Douglas, J.T. (2002). Targeted adenoviral vectors. Biochim Biophys Acta 1575, 1-14 12020813.
[14] Barquinero, J., Eixarch, H., and Pérez-Melgosa, M. (2004). Retroviral vectors: new applications for an old tool. Gene Ther 11, S3-S9 15454951.
[15] Barquinero, J., Segovia, J.C., Ramírez, M., Limón, A., Güenechea, G., Puig, T., Briones, J., García, J., and Bueren, J.A. (2000). Efficient transduction of human hematopoietic repopulating cells generating stable engraftment of transgene-expressing cells in NOD/SCID mice. Blood 95, 3085-3093 10807773.
[16] Bauer, T.R. Jr, Miller, A.D., and Hickstein, D.D. (1995). Improved transfer of the leukocyte integrin CD18 subunit into hematopoietic cell lines by using retroviral vectors having a gibbon ape leukemia virus envelope. Blood 86, 2379-2387 7662985.
[17] Baum, C., Hegewisch-Becker, S., Eckert, H.G., Stocking, C., and Ostertag, W. (1995). Novel retroviral vectors for efficient expression of the multidrug resistance (mdr-1) gene in early hematopoietic cells. J Virol 69, 7541-7547 7494260.
[18] Bellon, G., Michel-Calemard, L., Thouvenot, D., Jagneaux, V., Poitevin, F., Malcus, C., Accart, N., Layani, M.P., Aymard, M., Bernon, H., (1997). Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum Gene Ther 8, 15-25 8989991.
[19] Benihoud, K., Yeh, P., and Perricaudet, M. (1999). Adenovirus vectors for gene delivery. Curr Opin Biotechnol 10, 440-447 10508634.
[20] Berclaz, P.Y., Zsengellér, Z., Shibata, Y., Otake, K., Strasbaugh, S., Whitsett, J.A., and Trapnell, B.C. (2002). Endocytic internalization of adenovirus, nonspecific phagocytosis, and cytoskeletal organization are coordinately regulated in alveolar macrophages by GM-CSF and PU.1. J Immunol 169, 6332-6342 12444140.
[21] Berns, K.I., and Giraud, C. (1996). Biology of adeno-associated virus. Curr Top Microbiol Immunol 218, 1-23 8794242.
[22] Blankinship, M.J., Gregorevic, P., Allen, J.M., Harper, S.Q., Harper, H., Halbert, C.L., Miller, A.D., and Chamberlain, J.S. (2004). Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype 6. Mol Ther 10, 671-678 15451451.
[23] Bodine, D.M., Seidel, N.E., and Orlic, D. (1996). Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow. Blood 88, 89-97 8704206.
[24] Boothroyd, J.C., and Cross, G.A. (1982). Transcripts coding for variant surface glycoproteins of Trypanosoma brucei have a short, identical exon at their 5′ end. Gene 20, 281-289 7166234.
[25] Borgland, S.L., Bowen, G.P., Wong, N.C., Libermann, T.A., and Muruve, D.A. (2000). Adenovirus vector-induced expression of the C-X-C chemokine IP-10 is mediated through capsid-dependent activation of NF-kappaB. J Virol 74, 3941-3947 10756005.
[26] Boucher, R.C. (1994). Human airway ion transport. Part two. Am J Respir Crit Care Med 150, 581-593 8049852.
[27] Boucher, R.C. (1999). Status of gene therapy for cystic fibrosis lung disease. J Clin Invest 103, 441-445 10021450.
[28] Boucher, R.C., Stutts, M.J., Knowles, M.R., Cantley, L., and Gatzy, J.T. (1986). Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J Clin Invest 78, 1245-1252 3771796.
[29] Bragonzi, A., Dina, G., Villa, A., Calori, G., Biffi, A., Bordignon, C., Assael, B.M., and Conese, M. (2000). Biodistribution and transgene expression with nonviral cationic vector/DNA complexes in the lungs. Gene Ther 7, 1753-1760 11083497.
[30] Brunetti-Pierri, N., Palmer, D.J., Beaudet, A.L., Carey, K.D., Finegold, M., and Ng, P. (2004). Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther 15, 35-46 14965376.
[31] Cao, H., Koehler, D.R., and Hu, J. (2004). Adenoviral vectors for gene replacement therapy. Viral Immunol 17, 327-333 15357899.
[32] Cao, H., Yang, T., Li, X.F., Wu, J., Duan, C., Coates, A.L., and Hu, J. (2011). Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression. Gene Ther 18, 173-181 20882053.
[33] Cao, H.B., Wang, A., Martin, B., Koehler, D.R., Zeitlin, P.L., Tanawell, A.K., and Hu, J. (2005). Down-regulation of IL-8 expression in human airway epithelial cells through helper-dependent adenoviral-mediated RNA interference. Cell Res 15, 111-119 15740640.
[34] Caplen, N.J., Alton, E.W., Middleton, P.G., Dorin, J.R., Stevenson, B.J., Gao, X., Durham, S.R., Jeffery, P.K., Hodson, M.E., Coutelle, C., (1995). Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1, 39-46 7584951.
[35] Carter, B.J. (2004). Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol Ther 10, 981-989 15564130.
[36] Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., Gross, F., Yvon, E., Nusbaum, P., Selz, F., Hue, C., Certain, S., Casanova, J.L., (2000). Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669-672 10784449.
[37] Challita, P.M., Skelton, D., el-Khoueiry, A., Yu, X.J., Weinberg, K., and Kohn, D.B. (1995). Multiple modifications in cis elements of the long terminal repeat of retroviral vectors lead to increased expression and decreased DNA methylation in embryonic carcinoma cells. J Virol 69, 748-755 7815539.
[38] Chow, Y.H., O’Brodovich, H., Plumb, J., Wen, Y., Sohn, K.J., Lu, Z., Zhang, F., Lukacs, G.L., Tanswell, A.K., Hui, C.C., (1997). Development of an epithelium-specific expression cassette with human DNA regulatory elements for transgene expression in lung airways. Proc Natl Acad Sci U S A 94, 14695-14700 9405675.
[39] Chow, Y.H., Plumb, J., Wen, Y., Steer, B.M., Lu, Z., Buchwald, M., and Hu, J. (2000). Targeting transgene expression to airway epithelia and submucosal glands, prominent sites of human CFTR expression. Mol Ther 2, 359-367 11020351.
[40] Chu, Q., St George, J.A., Lukason, M., Cheng, S.H., Scheule, R.K., and Eastman, S.J. (2001). EGTA enhancement of adenovirus-mediated gene transfer to mouse tracheal epithelium in vivo. Hum Gene Ther 12, 455-467 11268280.
[41] Cideciyan, A.V. (2010). Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29, 398-427 20399883.
[42] Cideciyan, A.V., Aleman, T.S., Boye, S.L., Schwartz, S.B., Kaushal, S., Roman, A.J., Pang, J.J., Sumaroka, A., Windsor, E.A., Wilson, J.M., (2008). Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A 105, 15112-15117 18809924.
[43] Copreni, E., Penzo, M., Carrabino, S., and Conese, M. (2004). Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis. Gene Ther 11, S67-S75 15454960.
[44] Crystal, R. G., McElvaney, N. G., Rosenfeld, M. A., Chu, C. S., Mastrangeli, A., Hay, J. G., Brody, S. L., Jaffe, H. A., Eissa, N. T., and Danel, C. (1994). Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 8, 42-51 .
[45] Dai, Y., Schwarz, E.M., Gu, D., Zhang, W.W., Sarvetnick, N., and Verma, I.M. (1995). Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci U S A 92, 1401-1405 7877990.
[46] Duan, D., Yue, Y., and Engelhardt, J.F. (2001). Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol Ther 4, 383-391 11592843.
[47] Dunbar, C.E., Seidel, N.E., Doren, S., Sellers, S., Cline, A.P., Metzger, M.E., Agricola, B.A., Donahue, R.E., and Bodine, D.M. (1996). Improved retroviral gene transfer into murine and Rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor. Proc Natl Acad Sci U S A 93, 11871-11876 8876230.
[48] Ehrhardt, A., Xu, H., and Kay, M.A. (2003). Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in vivo. J Virol 77, 7689-7695 12805471.
[49] Evans, J.T., Kelly, P.F., O’Neill, E., and Garcia, J.V. (1999). Human cord blood CD34+CD38- cell transduction via lentivirus-based gene transfer vectors. Hum Gene Ther 10, 1479-1489 10395373.
[50] Fearon, D.T., and Locksley, R.M. (1996). The instructive role of innate immunity in the acquired immune response. Science 272, 50-53 8600536.
[51] Ferrari, S., Griesenbach, U., Iida, A., Farley, R., Wright, A.M., Zhu, J., Munkonge, F.M., Smith, S.N., You, J., Ban, H., (2007). Sendai virus-mediated CFTR gene transfer to the airway epithelium. Gene Ther 14, 1371-1379 17597790.
[52] Ferrari, S., Griesenbach, U., Shiraki-Iida, T., Shu, T., Hironaka, T., Hou, X., Williams, J., Zhu, J., Jeffery, P.K., Geddes, D.M., (2004). A defective nontransmissible recombinant Sendai virus mediates efficient gene transfer to airway epithelium in vivo. Gene Ther 11, 1659-1664 15284837.
[53] Flotte, T.R., Ng, P., Dylla, D.E., McCray, P.B. Jr, Wang, G., Kolls, J.K., and Hu, J. (2007). Viral vector-mediated and cell-based therapies for treatment of cystic fibrosis. Mol Ther 15, 229-241 17235299.
[54] Forsayeth, J.R., and Bankiewicz, K.S. (2011). AAV9: over the fence and into the woods . . .. Mol Ther 19, 1006-1007 21629257.
[55] Gao, G.P., Alvira, M.R., Wang, L., Calcedo, R., Johnston, J., and Wilson, J.M. (2002). Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 99, 11854-11859 12192090.
[56] Gaspar, H.B., Parsley, K.L., Howe, S., King, D., Gilmour, K.C., Sinclair, J., Brouns, G., Schmidt, M., Von Kalle, C., Barington, T., (2004). Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181-2187 15610804.
[57] Gill, D.R., Bazzani, R.P., and Hyde, S.C. (2010). Strategies for long-term expression of transgenes in the respiratory epithelium. Curr Opin Mol Ther 12, 386-393 20677089.
[58] Glimm, H., and Eaves, C.J. (1999). Direct evidence for multiple self-renewal divisions of human in vivo repopulating hematopoietic cells in short-term culture. Blood 94, 2161-2168 10498585.
[59] Glorioso, J.C., Goins, W.F., DeLuca, N., and Fink, D.J. (1994). Development of herpes simplex virus as a gene transfer vector for the nervous system. Gene Ther 1, S398542392.
[60] Grubb, B.R., Pickles, R.J., Ye, H., Yankaskas, J.R., Vick, R.N., Engelhardt, J.F., Wilson, J.M., Johnson, L.G., and Boucher, R.C. (1994). Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans. Nature 371, 802-806 7523956.
[61] Guilbault, C., Saeed, Z., Downey, G.P., and Radzioch, D. (2007). Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 36, 1-7 16888286.
[62] Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M.P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C.S., Pawliuk, R., Morillon, E., (2003). LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419 14564000.
[63] Hanenberg, H., Xiao, X.L., Dilloo, D., Hashino, K., Kato, I., and Williams, D.A. (1996). Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nat Med 2, 876-882 8705856.
[64] Hargrove, P.W., Vanin, E.F., Kurtzman, G.J., and Nienhuis, A.W. (1997). High-level globin gene expression mediated by a recombinant adeno-associated virus genome that contains the 3′ gamma globin gene regulatory element and integrates as tandem copies in erythroid cells. Blood 89, 2167-2175 9058741.
[65] Harvey, B. G., Leopold, P. L., Hackett, N. R., Grasso, T. M., Williams, P. M., Tucker, A. L., Kaner, R. J., Ferris, B., Gonda, I., Sweeney, T. D.,et al. (1999). Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J Clin Invest 104, 1245-1255 .
[66] Hennemann, B., Conneally, E., Pawliuk, R., Leboulch, P., Rose-John, S., Reid, D., Chuo, J.Y., Humphries, R.K., and Eaves, C.J. (1999). Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse repopulating cord blood cells through a systematic analysis of protocol variables. Exp Hematol 27, 817-825 10340397.
[67] Herzog, R.W., Cao, O., and Srivastava, A. (2010). Two decades of clinical gene therapy—success is finally mounting. Discov Med 9, 105-111 20193635.
[68] Hirsch, M.L., Agbandje-McKenna, M., and Samulski, R.J. (2010). Little vector, big gene transduction: fragmented genome reassembly of adeno-associated virus. Mol Ther 18, 6-8 20048740.
[69] Huang, X., and Yang, Y. (2009). Innate immune recognition of viruses and viral vectors. Hum Gene Ther 20, 293-301 19272012.
[70] Hyde, S.C., Pringle, I.A., Abdullah, S., Lawton, A.E., Davies, L.A., Varathalingam, A., Nunez-Alonso, G., Green, A.M., Bazzani, R.P., Sumner-Jones, S.G., (2008). CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol 26, 549-551 18438402.
[71] Hyde, S.C., Southern, K.W., Gileadi, U., Fitzjohn, E.M., Mofford, K.A., Waddell, B.E., Gooi, H.C., Goddard, C.A., Hannavy, K., Smyth, S.E., (2000). Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis. Gene Ther 7, 1156-1165 10918483.
[72] Jiang, Z., Feingold, E., Kochanek, S., and Clemens, P.R. (2002). Systemic delivery of a high-capacity adenoviral vector expressing mouse CTLA4Ig improves skeletal muscle gene therapy. Mol Ther 6, 369-376 12231173.
[73] Jornot, L., Petersen, H., Lusky, M., Pavirani, A., Moix, I., Morris, and Rochat, T (2001). Effects of first generation E1E3-deleted and second generation E1E3E4-deleted/modified adenovirus vectors on human endothelial cell death. Endothelium 8, 167-179 11824470.
[74] Joseph, P. M., O'Sullivan, B. P., Lapey, A., Dorkin, H., Oren, J., Balfour, R., Perricone, M. A., Rosenberg, M., Wadsworth, S. C., Smith, A. E.,et al. (2001). Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Hum Gene Ther 12, 1369-1382 .
[75] Kafri, T., Morgan, D., Krahl, T., Sarvetnick, N., Sherman, L., and Verma, I. (1998). Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. Proc Natl Acad Sci U S A 95, 11377-11382 9736744.
[76] Kalberer, C.P., Pawliuk, R., Imren, S., Bachelot, T., Takekoshi, K.J., Fabry, M., Eaves, C.J., London, I.M., Humphries, R.K., and Leboulch, P. (2000). Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta-globin in engrafted mice. Proc Natl Acad Sci U S A 97, 5411-5415 10792053.
[77] Kaplan, J.M., Pennington, S.E., St George, J.A., Woodworth, L.A., Fasbender, A., Marshall, J., Cheng, S.H., Wadsworth, S.C., Gregory, R.J., and Smith, A.E. (1998). Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential. Hum Gene Ther 9, 1469-1479 9681418.
[78] Kay, M.A., Holterman, A.X., Meuse, L., Gown, A., Ochs, H.D., Linsley, P.S., and Wilson, C.B. (1995). Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4Ig administration. Nat Genet 11, 191-197 7550348.
[79] Kearns, W.G., Afione, S.A., Fulmer, S.B., Pang, M.C., Erikson, D., Egan, M., Landrum, M.J., Flotte, T.R., and Cutting, G.R. (1996). Recombinant adeno-associated virus (AAV-CFTR) vectors do not integrate in a site-specific fashion in an immortalized epithelial cell line. Gene Ther 3, 748-755 8875221.
[80] Kim, I.H., Józkowicz, A., Piedra, P.A., Oka, K., and Chan, L. (2001). Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A 98, 13282-13287 11687662.
[81] Knowles, M.R., Hohneker, K.W., Zhou, Z., Olsen, J.C., Noah, T.L., Hu, P.C., Leigh, M.W., Engelhardt, J.F., Edwards, L.J., Jones, K.R., (1995). A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N Engl J Med 333, 823-831 7544439.
[82] Koehler, D.R., Frndova, H., Leung, K., Louca, E., Palmer, D., Ng, P., McKerlie, C., Cox, P., Coates, A.L., and Hu, J. (2005). Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter. J Gene Med 7, 1409-1420 15999396.
[83] Koehler, D.R., Hannam, V., Belcastro, R., Steer, B., Wen, Y., Post, M., Downey, G., Tanswell, A.K., and Hu, J. (2001a). Targeting transgene expression for cystic fibrosis gene therapy. Mol Ther 4, 58-65 11472107.
[84] Koehler, D.R., Hitt, M.M., and Hu, J. (2001b). Challenges and strategies for cystic fibrosis lung gene therapy. Mol Ther 4, 84-91 11482978.
[85] Koehler, D.R., Sajjan, U., Chow, Y.H., Martin, B., Kent, G., Tanswell, A.K., McKerlie, C., Forstner, J.F., and Hu, J. (2003). Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia. Proc Natl Acad Sci U S A 100, 15364-15369 14673110.
[86] Koenig, M., Hoffman, E.P., Bertelson, C.J., Monaco, A.P., Feener, C., and Kunkel, L.M. (1987). Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50, 509-517 3607877.
[87] Kojaoghlanian, T., Flomenberg, P., and Horwitz, M.S. (2003). The impact of adenovirus infection on the immunocompromised host. Rev Med Virol 13, 155-171 12740831.
[88] Kollen, W.J., Mulberg, A.E., Wei, X., Sugita, M., Raghuram, V., Wang, J., Foskett, J.K., Glick, M.C., and Scanlin, T.F. (1999). High-efficiency transfer of cystic fibrosis transmembrane conductance regulator cDNA into cystic fibrosis airway cells in culture using lactosylated polylysine as a vector. Hum Gene Ther 10, 615-622 10094204.
[89] Kotin, R.M., Siniscalco, M., Samulski, R.J., Zhu, X.D., Hunter, L., Laughlin, C.A., McLaughlin, S., Muzyczka, N., Rocchi, M., and Berns, K.I. (1990). Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A 87, 2211-2215 2156265.
[90] Kushwah, R., Oliver, J.R., Cao, H., and Hu, J. (2007). Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways. Gene Ther 14, 1243-1248 17525704.
[91] Lee, B.H., Kushwah, R., Wu, J., Ng, P., Palaniyar, N., Grinstein, S., Philpott, D.J., and Hu, J. (2010). Adenoviral vectors stimulate innate immune responses in macrophages through cross-talk with epithelial cells. Immunol Lett 134, 93-102 20850478.
[92] Li, X., Li, W., Dai, X., Kong, F., Zheng, Q., Zhou, X., Lü, F., Chang, B., Rohrer, B., Hauswirth, W.W., (2011). Gene therapy rescues cone structure and function in the 3-month-old rd12 mouse: a model for midcourse RPE65 leber congenital amaurosis. Invest Ophthalmol Vis Sci 52, 7-15 21169527.
[93] Liang, X.H., Haritan, A., Uliel, S., and Michaeli, S. (2003). trans and cis splicing in trypanosomatids: mechanism, factors, and regulation. Eukaryot Cell 2, 830-840 14555465.
[94] Limberis, M., Anson, D.S., Fuller, M., and Parsons, D.W. (2002). Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer. Hum Gene Ther 13, 1961-1970 12427306.
[95] Mack, C.A., Song, W.R., Carpenter, H., Wickham, T.J., Kovesdi, I., Harvey, B.G., Magovern, C.J., Isom, O.W., Rosengart, T., Falck-Pedersen, E., (1997). Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 8, 99-109 8989999.
[96] Maguire, A.M., Simonelli, F., Pierce, E.A., Pugh, E.N. Jr, Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K.A., Testa, F., Surace, E.M., (2008). Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358, 2240-2248 18441370.
[97] Maione, D., Della Rocca, C., Giannetti, P., D’Arrigo, R., Liberatoscioli, L., Franlin, L.L., Sandig, V., Ciliberto, G., La Monica, N., and Savino, R. (2001). An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus. Proc Natl Acad Sci U S A 98, 5986-5991 11353820.
[98] Mastrangeli, A., Harvey, B.G., Yao, J., Wolff, G., Kovesdi, I., Crystal, R.G., and Falck-Pedersen, E. (1996). “Sero-switch” adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum Gene Ther 7, 79-87 8825871.
[99] Mátrai, J., Chuah, M.K., and VandenDriessche, T. (2010). Recent advances in lentiviral vector development and applications. Mol Ther 18, 477-490 20087315.
[100] Matsushima, K., Morishita, K., Yoshimura, T., Lavu, S., Kobayashi, Y., Lew, W., Appella, E., Kung, H.F., Leonard, E.J., and Oppenheim, J.J. (1988). Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med 167, 1883-1893 3260265.
[101] McCoy, R.D., Davidson, B.L., Roessler, B.J., Huffnagle, G.B., Janich, S.L., Laing, T.J., and Simon, R.H. (1995). Pulmonary inflammation induced by incomplete or inactivated adenoviral particles. Hum Gene Ther 6, 1553-1560 8664380.
[102] Michou, A.I., Santoro, L., Christ, M., Julliard, V., Pavirani, A., and Mehtali, M. (1997). Adenovirus-mediated gene transfer: influence of transgene, mouse strain and type of immune response on persistence of transgene expression. Gene Ther 4, 473-482 9274725.
[103] Moritz, T., Dutt, P., Xiao, X., Carstanjen, D., Vik, T., Hanenberg, H., and Williams, D.A. (1996). Fibronectin improves transduction of reconstituting hematopoietic stem cells by retroviral vectors: evidence of direct viral binding to chymotryptic carboxy-terminal fragments. Blood 88, 855-862 8704241.
[104] Morral, N., O’Neal, W.K., Rice, K., Leland, M.M., Piedra, P.A., Aguilar-Córdova, E., Carey, K.D., Beaudet, A.L., and Langston, C. (2002). Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum Gene Ther 13, 143-154 11779418.
[105] Morsy, M.A., Gu, M., Motzel, S., Zhao, J., Lin, J., Su, Q., Allen, H., Franlin, L., Parks, R.J., Graham, F.L., (1998). An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci U S A 95, 7866-7871 9653106.
[106] Moss, R.B., Rodman, D., Spencer, L.T., Aitken, M.L., Zeitlin, P.L., Waltz, D., Milla, C., Brody, A.S., Clancy, J.P., Ramsey, B., (2004). Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 125, 509-521 14769732.
[107] Noone, P.G., Hohneker, K.W., Zhou, Z., Johnson, L.G., Foy, C., Gipson, C., Jones, K., Noah, T.L., Leigh, M.W., Schwartzbach, C., (2000). Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol Ther 1, 105-114 10933918.
[108] O’Neal, W.K., Rose, E., Zhou, H., Langston, C., Rice, K., Carey, D., and Beaudet, A.L. (2000). Multiple advantages of alpha-fetoprotein as a marker for in vivo gene transfer. Mol Ther 2, 640-648 11124066.
[109] Oshima, R.G., Abrams, L., and Kulesh, D. (1990). Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. Genes Dev 4, 835-848 1696235.
[110] Overbaugh, J., Miller, A.D., and Eiden, M.V. (2001). Receptors and entry cofactors for retroviruses include single and multiple transmembrane-spanning proteins as well as newly described glycophosphatidylinositol-anchored and secreted proteins.[table of contents.] Microbiol Mol Biol Rev 65, 371-389 11528001.
[111] Palmer, D., and Ng, P. (2003). Improved system for helper-dependent adenoviral vector production. Mol Ther 8, 846-852 14599819.
[112] Parks, R.J. (2000). Improvements in adenoviral vector technology: overcoming barriers for gene therapy. Clin Genet 58, 1-11 10945654.
[113] Pearson, H. (2009). Human genetics: One gene, twenty years. Nature 460, 164-169 19587741.
[114] Pergolizzi, R.G., and Crystal, R.G. (2004). Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing. C R Biol 327, 695-709 15506518.
[115] Perricone, M. A., Morris, J. E., Pavelka, K., Plog, M. S., O'Sullivan, B. P., Joseph, P. M., Dorkin, H., Lapey, A., Balfour, R., Meeker, D. P.,et al. (2001). Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum Gene Ther 12, 1383-1394 .
[116] Pickles, R.J., Fahrner, J.A., Petrella, J.M., Boucher, R.C., and Bergelson, J.M. (2000). 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 74, 6050-6057 10846088.
[117] Porteous, D.J., Dorin, J.R., McLachlan, G., Davidson-Smith, H., Davidson, H., Stevenson, B.J., Carothers, A.D., Wallace, W.A., Moralee, S., Hoenes, C., (1997). Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther 4, 210-218 9135734.
[118] Pringle, C.R. (1999). Virus taxonomy—1999. The universal system of virus taxonomy, updated to include the new proposals ratified by the International Committee on Taxonomy of Viruses during 1998. Arch Virol 144, 421-429 10470265.
[119] Pupita, F., and Barone, A. (1983). Clinical pharmacology of DEAE-dextran for long-term administration (one year). Int J Clin Pharmacol Res 3, 287-293 6206004.
[120] Qin, L., Ding, Y., Pahud, D.R., Chang, E., Imperiale, M.J., and Bromberg, J.S. (1997). Promoter attenuation in gene therapy: interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum Gene Ther 8, 2019-2029 9414251.
[121] Raper, S.E., Chirmule, N., Lee, F.S., Wivel, N.A., Bagg, A., Gao, G.P., Wilson, J.M., and Batshaw, M.L. (2003). Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 80, 148-158 14567964.
[122] Reich, S.J., Auricchio, A., Hildinger, M., Glover, E., Maguire, A.M., Wilson, J.M., and Bennett, J. (2003). Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene therapy. Hum Gene Ther 14, 37-44 12573057.
[123] Rogers, C.S., Stoltz, D.A., Meyerholz, D.K., Ostedgaard, L.S., Rokhlina, T., Taft, P.J., Rogan, M.P., Pezzulo, A.A., Karp, P.H., Itani, O.A., (2008). Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321, 1837-1841 18818360.
[124] Rogers, S., and Moore, M. (1963). Studies of the mechanism of action of the Shope rabbit papilloma virus. I. Concerning the nature of the induction of arginase in the infected cells. J Exp Med 117, 521-542 13982404.
[125] Rommens, J.M., Iannuzzi, M.C., Kerem, B., Drumm, M.L., Melmer, G., Dean, M., Rozmahel, R., Cole, J.L., Kennedy, D., Hidaka, N., (1989). Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059-1065 2772657.
[126] Ruiz, F.E., Clancy, J.P., Perricone, M.A., Bebok, Z., Hong, J.S., Cheng, S.H., Meeker, D.P., Young, K.R., Schoumacher, R.A., Weatherly, M.R., (2001). A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum Gene Ther 12, 751-761 11339892.
[127] Salvi, S., and Holgate, S.T. (1999). Could the airway epithelium play an important role in mucosal immunoglobulin A production? Clin Exp Allergy 29, 1597-1605 10594535.
[128] Scaria, A., St George, J.A., Gregory, R.J., Noelle, R.J., Wadsworth, S.C., Smith, A.E., and Kaplan, J.M. (1997). Antibody to CD40 ligand inhibits both humoral and cellular immune responses to adenoviral vectors and facilitates repeated administration to mouse airway. Gene Ther 4, 611-617 9231078.
[129] Schaack, J., Bennett, M.L., Colbert, J.D., Torres, A.V., Clayton, G.H., Ornelles, D., and Moorhead, J. (2004). E1A and E1B proteins inhibit inflammation induced by adenovirus. Proc Natl Acad Sci U S A 101, 3124-3129 14976240.
[130] Schnepp, B.C., Clark, K.R., Klemanski, D.L., Pacak, C.A., and Johnson, P.R. (2003). Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol 77, 3495-3504 12610125.
[131] Singh, B., and de la Concha-Bermejillo, A. (1998). Gadolinium chloride removes pulmonary intravascular macrophages and curtails the degree of ovine lentivirus-induced lymphoid interstitial pneumonia. Int J Exp Pathol 79, 151-162 9741357.
[132] Singhal, A., and Huang, L. (1994). Gene transfer in Mammalian using liposomes as carriers. In: Gene Therapeutics . Wolff J. A. ed. Boston: Birkhauser, 118-142 .
[133] Sinn, P.L., Burnight, E.R., and McCray, P.B. Jr. (2009). Progress and prospects: prospects of repeated pulmonary administration of viral vectors. Gene Ther 16, 1059-1065 19641533.
[134] Sinn, P.L., Hickey, M.A., Staber, P.D., Dylla, D.E., Jeffers, S.A., Davidson, B.L., Sanders, D.A., and McCray, P.B. Jr. (2003). Lentivirus vectors pseudotyped with filoviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha. J Virol 77, 5902-5910 12719583.
[135] Sirninger, J., Muller, C., Braag, S., Tang, Q., Yue, H., Detrisac, C., Ferkol, T., Guggino, W.B., and Flotte, T.R. (2004). Functional characterization of a recombinant adeno-associated virus 5-pseudotyped cystic fibrosis transmembrane conductance regulator vector. Hum Gene Ther 15, 832-841 15353038.
[136] Smith, A.E. (1995). Viral vectors in gene therapy. Annu Rev Microbiol 49, 807-838 8561480.
[137] Smith, T., Idamakanti, N., Kylefjord, H., Rollence, M., King, L., Kaloss, M., Kaleko, M., and Stevenson, S.C. (2002). In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. Mol Ther 5, 770-779 12027562.
[138] Snouwaert, J.N., Brigman, K.K., Latour, A.M., Iraj, E., Schwab, U., Gilmour, M.I., and Koller, B.H. (1995). A murine model of cystic fibrosis. Am J Respir Crit Care Med 151, S59-S64 7533607.
[139] Spina, D. (1998). Epithelium smooth muscle regulation and interactions. Am J Respir Crit Care Med 158, S141-S145 9817737.
[140] St George, J.A. (2003). Gene therapy progress and prospects: adenoviral vectors. Gene Ther 10, 1135-1141 12833122.
[141] Stein, L., Roy, K., Lei, L., and Kaushal, S. (2011). Clinical gene therapy for the treatment of RPE65-associated Leber congenital amaurosis. Expert Opin Biol Ther 11, 429-439 21299439.
[142] Stoltz, D.A., Meyerholz, D.K., Pezzulo, A.A., Ramachandran, S., Rogan, M.P., Davis, G.J., Hanfland, R.A., Wohlford-Lenane, C., Dohrn, C.L., Bartlett, J.A., (2010). Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med 2, 29ra3120427821.
[143] Summerford, C., and Samulski, R.J. (1998). Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 72, 1438-1445 9445046.
[144] Sung, R.S., Qin, L., and Bromberg, J.S. (2001). TNFalpha and IFNgamma induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression. Mol Ther 3, 757-767 11356080.
[145] Suzuki, H., Kurihara, Y., Takeya, M., Kamada, N., Kataoka, M., Jishage, K., Ueda, O., Sakaguchi, H., Higashi, T., Suzuki, T., (1997). A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386, 292-296 9069289.
[146] Terheggen, H.G., Lowenthal, A., Lavinha, F., Colombo, J.P., and Rogers, S. (1975). Unsuccessful trial of gene replacement in arginase deficiency. Z Kinderheilkd 119, 1-3 164740.
[147] Thepen, T., McMenamin, C., Oliver, J., Kraal, G., and Holt, P.G. (1991). Regulation of immune response to inhaled antigen by alveolar macrophages: differential effects of in vivo alveolar macrophage elimination on the induction of tolerance vs. immunity. Eur J Immunol 21, 2845-2850 1936124.
[148] Toietta, G., Koehler, D.R., Finegold, M.J., Lee, B., Hu, J., and Beaudet, A.L. (2003). Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter. Mol Ther 7, 649-658 12718908.
[149] Tripathy, S.K., Black, H.B., Goldwasser, E., and Leiden, J.M. (1996). Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 2, 545-550 8616713.
[150] Tsui, L.C. (1995). The cystic fibrosis transmembrane conductance regulator gene. Am J Respir Crit Care Med 151, S47-S53 7533605.
[151] van der Loo, J.C., Liu, B.L., Goldman, A.I., Buckley, S.M., and Chrudimsky, K.S. (2002). Optimization of gene transfer into primitive human hematopoietic cells of granulocyte-colony stimulating factor-mobilized peripheral blood using low-dose cytokines and comparison of a gibbon ape leukemia virus versus an RD114-pseudotyped retroviral vector. Hum Gene Ther 13, 1317-1330 12162814.
[152] Veena, P., Traycoff, C.M., Williams, D.A., McMahel, J., Rice, S., Cornetta, K., and Srour, E.F. (1998). Delayed targeting of cytokine-nonresponsive human bone marrow CD34(+) cells with retrovirus-mediated gene transfer enhances transduction efficiency and long-term expression of transduced genes. Blood 91, 3693-3701 9573006.
[153] Waddington, S.N., McVey, J.H., Bhella, D., Parker, A.L., Barker, K., Atoda, H., Pink, R., Buckley, S.M., Greig, J.A., Denby, L., (2008). Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 132, 397-409 18267072.
[154] Wagner, J.A., Messner, A.H., Moran, M.L., Daifuku, R., Kouyama, K., Desch, J.K., Manley, S., Norbash, A.M., Conrad, C.K., Friborg, S., (1999). Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109, 266-274 10890777.
[155] Wang, B., Li, J., and Xiao, X. (2000). Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci U S A 97, 13714-13719 11095710.
[156] Wilson, C.B., Embree, L.J., Schowalter, D., Albert, R., Aruffo, A., Hollenbaugh, D., Linsley, P., and Kay, M.A. (1998). Transient inhibition of CD28 and CD40 ligand interactions prolongs adenovirus-mediated transgene expression in the lung and facilitates expression after secondary vector administration. J Virol 72, 7542-7550 9696851.
[157] Wivel, N.A., Gao, P.-G., and Wilson, J.M. (1999). Adenosvirus vectors. In: The Development of Human Gene Therapy . San Diego, CA: Cold Spring Harbor Laboratory Press.
[158] Wolff, J.A., and Lederberg, J. (1994). An early history of gene transfer and therapy. Hum Gene Ther 5, 469-480 8049304.
[159] Worgall, S., Leopold, P.L., Wolff, G., Ferris, B., Van Roijen, N., and Crystal, R.G. (1997). Role of alveolar macrophages in rapid elimination of adenovirus vectors administered to the epithelial surface of the respiratory tract. Hum Gene Ther 8, 1675-1684 9322870.
[160] Yam, P.Y., Yee, J.K., Ito, J.I., Sniecinski, I., Doroshow, J.H., Forman, S.J., and Zaia, J.A. (1998). Comparison of amphotropic and pseudotyped VSV-G retroviral transduction in human CD34+ peripheral blood progenitor cells from adult donors with HIV-1 infection or cancer. Exp Hematol 26, 962-968 9728931.
[161] Yamashita, K., Masunaga, T., Yanagida, N., Takehara, M., Hashimoto, T., Kobayashi, T., Echizenya, H., Hua, N., Fujita, M., Murakami, M., (2003). Long-term acceptance of rat cardiac allografts on the basis of adenovirus mediated CD40Ig plus CTLA4Ig gene therapies. Transplantation 76, 1089-1096 14557758.
[162] Yan, Z., Zhang, Y., Duan, D., and Engelhardt, J.F. (2000). Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. Proc Natl Acad Sci U S A 97, 6716-6721 10841568.
[163] Yang, T., Duan, R., Cao, H., Lee, B.H., Xia, C., Chang, Z., Keith Tanswell, A., and Hu, J. (2010). Development of an inflammation-inducible gene expression system using helper-dependent adenoviral vectors. J Gene Med 12, 832-839 20848669.
[164] Yang, Y., Jooss, K.U., Su, Q., Ertl, H.C., and Wilson, J.M. (1996). Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther 3, 137-144 8867861.
[165] Yang, Y., Li, Q., Ertl, H.C., and Wilson, J.M. (1995). Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol 69, 2004-2015 7884845.
[166] Yu, S.F., von Rüden, T., Kantoff, P.W., Garber, C., Seiberg, M., Rüther, U., Anderson, W.F., Wagner, E.F., and Gilboa, E. (1986). Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cells. Proc Natl Acad Sci U S A 83, 3194-3198 3458176.
[167] Zabner, J., Cheng, S.H., Meeker, D., Launspach, J., Balfour, R., Perricone, M.A., Morris, J.E., Marshall, J., Fasbender, A., Smith, A.E., (1997). Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J Clin Invest 100, 1529-1537 9294121.
[168] Zabner, J., Couture, L.A., Gregory, R.J., Graham, S.M., Smith, A.E., and Welsh, M.J. (1993). Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207-216 7691415.
[169] Zabner, J., Fasbender, A.J., Moninger, T., Poellinger, K.A., and Welsh, M.J. (1995). Cellular and molecular barriers to gene transfer by a cationic lipid. J Biol Chem 270, 18997-19007 7642560.
[170] Zsengellér, Z., Otake, K., Hossain, S.A., Berclaz, P.Y., and Trapnell, B.C. (2000). Internalization of adenovirus by alveolar macrophages initiates early proinflammatory signaling during acute respiratory tract infection. J Virol 74, 9655-9667 11000238.