Abstract
Non-viral gene therapy now includes a number of different strategies ranging from direct intramuscular injection of naked DNA to the systemic or local administration of formulations comprising DNA and lipid, proteins, peptides or polymers. While the main limitation of non-viral gene transfer methods is their relatively low efficiency in vivo, both preclinical and clinical studies indicate that these methods exhibit safety profiles similar to conventional pharmaceutical and biological products. Cationic liposome-based gene therapy has been extensively studied for the treatment of the genetic disease cystic fibrosis, where research has reached the stage of clinical trials. Non-viral gene delivery has also been studied with a view to developing treatment for the acute lung injury and pulmonary oedema associated with the adult respiratory distress syndrome (ARDS). In this chapter, following a brief overview of non-viral gene transfer, the progress of both clinical studies for CF gene therapy and preclinical studies for pulmonary oedema are described.
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Literature Cited
Ferrari S, Moro E, Pentenazzo A et al. Exgen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo. Gene Ther. 1997;4:11000–1106.
Rudolph C, Lausier J, Naundorf S, et al. In vivo delivery to the lung using polyethylenimine and fractured polyamidoamine dendrimers. J Gene Med. 2000;2:269–278.
Sternberg B, Sorgi FL, Huang L. New structures in complex formation between DNA and cationic liposomes visualised by freexe-fracture electron microscopy. FEBSLett. 1994;356:361–366.
Feigner PL, Gadek TR, Holm M, et al. Lipofection: A highly efficient lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA. 84,1987;7413–7417.
Feigner JH, Kumar R, Sridhar CN, et al. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J BiolChem. 1994;269:2550–2561.
Leventis R, Silvius JR. Interactions of mammalian cells with lipid dispersions containing novel metabolizable cationic amphiphiles. Biochim Biophys Acta. 1990;1023:124–132
Gao X, Huang L. A novel cationic liposome for efficient transfection of mammalian cells. Biochem Biophys Res Comm. 1991;179, 280–285.
Lee ER, Marshall J, Siegel et al. Detailed analysis of structure and formulations of cationic lipids for efficient gene transfer to the lung. Hum Gene Ther. 1996;7:1701–1717.
Labat-Moleur F, Steffan AM, Brisson C, et al. An electron microscopy study into the mechanism of gene transfer with polyamines. Gene Ther. 1996;3:1010–1017.
Kitson C, Angel B, Judd D, et al. The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium. Gene Ther. 1999;6:534–546.
Xu Y, Szoka F. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochem. 1996;35:5616–5623.
Wilson GL, Dean BS, Wang G, et al. Nuclear import of plasmid DNA in digitonin-permeabilised cells requires both cytoplamsic factors and specific DNA sequences. J Biol Chem. 1999.274:22025–22032.
Riordan JR, Rommens JM, Kerem BS, et al. Identification of the Cystic Fibrosis Gene: Cloning and characterization of complementary DNA. Science. 1989;245, 1066–1073.
Welsh MJ. Abnormal regulation of ion channels in cystic fibrosis. FASEBJ. 1990;4:2718–2725.
Knowles MR, Gatzy JT, Boucher RC. Increased bioelelectric potential difference across respiratory epithelia in cystic fibrosis. New Engl J Med. 1981;305:1489–1495.
Drumm M, Pope HA, Cliff, WH, et al. Correction of the CF defect in vitro by retrovirus-mediated gene transfer. Cell. 1999;62:1227–1230.
Rich DP, Anderson MP, Gregory RJ, 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.
Hyde SC, Gill DR, Higgins CF, et al. Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature. 1993;362:250–255.
Alton EWFW, Middleton PG, Caplen NJ, et al. Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mice. Nat Genet. 1993;5:135–142.
Zabner J, Couture RA, Gregory RJ, et al. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell. 1993; 75:207–216.
Crystal RG, McElvanehy LG, Rosenfeld MA, et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat. Genet. 1994;8:42–51.
Boucher RC, Knowles MR, Johnson LG, et al. Gene therapy for cystic fibrosis using El-deleted adenovirus: a phase I trial in the nasal cavity. Hum Gene Ther. 1994;5:615–619.
Caplen NJ, Alton EW, Middleton PG, et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med. 1995;1:39–46.
Gill DR, Southern KW, Mofford KA, et al. A placebo controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 1997;4:199–209.
Porteus DJ, Dorin JR, 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.
Zabner J, Cheng S, Meeker D, et al. Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelium in vivo. J Clin Invest. 1997;100:1529–1537.
Alton EWFW, 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.
Hyde SC, Southern KW, Gileadi U, et al. Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 2000;7:1156–1165.
Sorcher EJ, Logan JJ, Frizzell RA, et al. Gene therapy for cystic fibrosis using cationic liposome-mediated gene transfer: a phase I trial of safety and efficacy in the nasal airway. Hum Gene Ther. 1994:5:1259–1277.
Noone PG, Hohneker KW, Zhou Z, et al. Safety and efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol Med. 2000;1:105–114.
Middleton PG, Geddes DM, Alton EWFW. Protocols for in vivo measurement of the ion transport defects in cystic fibrosis epithelium. EurRespJ. 1994;7:2050–2056.
Stern M, Munkonge F, Caplen NJ et al. Quantitative fluorescent measurements of chloride secretion in native airway epithelium from CF andnon-CF subjects. Gene Ther. 1995;2:766–774.
Chadwick SL, Kingston HD, Stern M, et al. Safety of a single aerosol administration of escalating doses of the cationic lipid 67/DOPE/DMPE-PEG500 formulation to the lungs of normal volunteers. Gene Ther. 1997; 4:937–942.
Davies J, Stern M, Dewar A, et al. CFTR gene transfer reduces the binding of pseudomonas aeruginosa to cytic fibrosis epithelium. Am J Resp Cell Mol Biol. 1997;16:657–663.
Schwartz DA, Quinn TJ, Thome PS, et al. CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest. 1997;100:68–73.
Stem M, Caplen NJ, Browning JE, et al. The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro. Gene Ther. 1998;5:91–98.
Matsui H, Johnson LG, Randell SH, et al. Loss of binding and entry of liposome-DNA complexes decreases transfection efficiency in differentiated airway epithelial cells. J Biol Chem. 1997;272:1117–1126.
Wagner E, Zenke M, Cotten M, et al. Transferrin-polycation conjugates as carriers for DNA uptake into cells. Proc Natl Acad Sci USA. 1990;87:3410–3414.
Cotton M, Langle-Rouault R, Kirlappos H, et al. Transferrin-polycation-mediated introduction of DNA into human leukemic cells: Stimulation by agents that affect the survival of transfected DNA or modulate transferrin receptor levels. Proc Natl Acad Sci USA. 1990;87:4033–4037.
Kollen WJ, Mulberg AE, Wei X, et al. High efficiency transfer of cystic fibrosis transmembrane conductance regulator into cystic fibrosis airway cells in culture using lactoslyated polylysine as a vector. Hum Gene Ther. 10:615–622.
Truong-Le VL, August JT, Leong KW. Controlled gene delivery by DNA-gelatin nanospheres. Hum Gene Ther. 1998;8:817–825.
Blessing T, Remy JS, Behr JP. Monomolecular collapse of plasmid DNA inot stable virus-like particles. Proc Natl Acad Sci USA. 1998;95:1427–1431.
Yonemitsu Y, Kaneda Y, Muraishi A, et al. HVJ (Sendai virus)-cationic liposomes: a novel and potentially effectiver liposome-mediated technique for gene transfer to the airway epithelium. Gene Ther. 1997;4:631–638.
Johnson LG, Olsen JC, Sarkadi B. et al. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nat Genet. 1992;2:21–25.
Johnson LG, Boyles SE, Wilson J, et al. Normalisation 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;95:1377–82.
Matthay MA, Landholt CC, Staub N. Differential liquid and protein clearance from the alveoli of anaesthetized sheep. J Appl Physiol. 1982;53:96–104.
Berthiaume Y, Staub NC, Matthay MA. Beta adrenergic agonists increase lung liquid clearance in anesthetized sheep. J Clin Invest. 1987;79:335–343.
Matthay MA, Berthiaume Y, Staub NC. Long term clearance of liquid and protein from the lungs of anaesthetized sheep. J Appl Physiol. 1985;59:928–934.
Sakuma T Okaniwa G, Nakada T, et al. Alveolar fluid clearance in the resected human lung. Am Rev Resp Dis. 1994; 150:305–310.
O Brodovich HM. The role of active Na+ transport by lung epithelium in the clearamce of airspace fluid. New Horizons. 1995;3:240–247.
Matthay MA, Wiener-Kronich JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Resp Dis. 1990;142:1250–1257.
Famborough DM. The sodium pump becomes a family. Trends Neurosci. 1988;1:325–328.
Ewart HS, Klip A. Hormonal regulation of the Na+K+-ATPase: mechanisms underlying rapid and sustained changes in pump activity. AmJPhysiol. 1988;269:C295–311.
Lingrel JB, Orlowski J, Skull MM, et al. Molecular genetics of NaK ATPase. Prog Nucleic Acid Res 1990;38:37–89.
O Brodovich H, Staub N, Rossier BC, et al. Ontogeny of α_, and β_, isoforms of Na+K+ ATPase in fetal rat distal lung epithelium. Am J Physiol 1993;264:C1137–1143.
McDonough, Geering AK, Farley RA. The sodium pump needs its β subunit. Faseb J. 1990;4:1598–1605.
Horowitz B, Eakle KA, Scheiner-Bobis G, et al. Synthesis and assembly of functional mammalian Na,K-ATPase in yeast. J Biol Chem. 1990;265:4189–4192.
Orlowski J, Lingrel JB. Tissue specific and developmental regulation of rat NaK ATPase catalytic alpha isoform and beta subunit mRNA s. J Biol Chem. 1998;263:10436–10442.
Crump RG, Askew GR, Wert SE, et al. In situ localization of sodium-potassium ATPase mRNA in developing mouse lung epithelium. Am J Physiol. 1995;269:L299–308.
Chapman DL, Widdicombe JH, Bland RD. Developmental differences in rabbit lung epithelial cell Na+K+ATPase. Am J Physiol. 1990; 259: L481–487.
Kim KJ, Cheek J, Crandall E. Contribution of active Na+ and CI- flux to net ion transport of alveolar epithelium. Resp Physiol. 1991; 85: 245–256.
Cheek JK, Kim J, Crandall E. Tight monolayers of rat alveolar epithelial cells: bioelectric properties and active sodium transport. Am J Physiol. 1989; 256:C688–693.
Goddman BK, Kim J, Crandall E. Evidence for active sodium transport across alveolar epithelium of isolated rat lung. J Appl Physiol. 1987;62:2460–2466.
Basset G, Crone C, Saumon G. Significance of active ion transport in transalveolar water absorption: a study on isolated rat lung. J Physiol Lond. 1987;384:311–324.
Yue G, Matalon S. Mechanisms and sequelae of increased alveolar fluid clearance in hyperoxic rats. Am J Physiol. 1997;272:L407–412.
Pittet JF, Wiener-Kronish JP, McElroy MC, et al. Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats. J Clin Invest. 1994;94:663–671.
Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelium and epithelial barriers of the lung in sheep to escherichia coli endotoxin. J Clin Invest. 1991;88:864–875.
Sakuma T, Pittet JF, Jayr C, Matthay MA. Alveolar liquid and protein clearance in the absence of blood flow or ventilation in sheep. J Appl Physiol. 1993;74:176–185.
Zuege D, Suzuki S, Berthiaume Y. Increase of lung sodium-potassium ATPase activity during recovery from high permeability pulmonary edema. Am J Physiol. 1996; 271:L896–L909.
Factor P, Saldias F, Ridge K, et al. Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase Pi subunit gene. J Clin Invest 1998; 102:1421–1430.
Stern M, Ulrich K, Robinson C, et al. Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema. Gene Ther. 2000; 7:960–966.
Hillery E, Cheng S, Geddes DM, et al. Effects of altering dose on cationic liposome-mediated gene transfer to the respiratory epithelium. Gene Ther. 1999;6:1313–1316.
Canessa CM, Schild L, Buell G. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994;367:463–467.
Kundu S, Herman SJ, Winton TL. Reperfusion edema after lung transplantation: radiographic manifestations. Radiology. 1998;206:75–80.
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Stern, M., Alton, E. (2001). Non-Viral Gene Therapy for Pulmonary Disease. In: Factor, P. (eds) Gene Therapy for Acute and Acquired Diseases. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1667-5_3
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DOI: https://doi.org/10.1007/978-1-4615-1667-5_3
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