Abstract
Gene therapy vectors based on viruses are the most effective gene delivery systems in use today and although efficient at gene transfer their potential toxicity (Hacein-Bey-Abina et al., Science 302:415–419, 2003) provides impetus for the development of safer non-viral alternatives. An ideal vector for human gene therapy should deliver sustainable therapeutic levels of gene expression without affecting the viability of the host at either the cellular or somatic level. Vectors, which comprise entirely human elements, may provide the most suitable method of achieving this. Non-viral vectors are attractive alternatives to viral gene delivery systems because of their low toxicity, relatively easy production, and great versatility. The development of more efficient, economically prepared, and safer gene delivery vectors is a crucial prerequisite for their successful clinical application and remains a primary strategic task of gene therapy research.
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References
Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419
Wolff JA, Malone RW, Williams P et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465–1468
Hickman MA, Malone RW, Lehmann-Bruinsma K et al (1994) Gene expression following direct injection of DNA into liver. Hum Gene Ther 5: 1477–1483
Budker V, Zhang G, Knechtle S et al (1996) Naked DNA delivered intraportally expresses efficiently in hepatocytes. Gene Ther 3:593–598
Choate KA, Khavari PA (1997) Direct cutaneous gene delivery in a human genetic skin disease. Hum Gene Ther 8:1659–1665
Meyer KB, Thompson MM, Levy MY et al (1995) Intratracheal gene delivery to the mouse airway: characterization of plasmid DNA expression and pharmacokinetics. Gene Ther 2: 450–460
Reilly JP, Grise MA, Fortuin FD et al (2005) Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no-option patients. J Interv Cardiol 18:27–31
Schwartz B, Benoist C, Abdallah B et al (1996) Gene transfer by naked DNA into adult mouse brain. Gene Ther 3:405–411
Zelenin AV, Kolesnikov VA, Tarasenko OA et al (1997) Bacterial beta-galactosidase and human dystrophin genes are expressed in mouse skeletal muscle fibers after ballistic transfection. FEBS Lett 414:319–322
Mehier-Humbert S, Guy RH (2005) Physical methods for gene transfer: improving the kinetics of gene delivery into cells. Adv Drug Deliv Rev 57:733–753
Gao X, Kim KS, Liu D (2007) Nonviral gene delivery: what we know and what is next. AAPS J 9:E92–104
Taniyama Y, Tachibana K, Hiraoka K et al (2002) Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation 105:1233–1239
Taniyama Y, Tachibana K, Hiraoka K et al (2002) Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle. Gene Ther 9: 372–380
Lawrie A, Brisken AF, Francis SE et al (2000) Microbubble-enhanced ultrasound for vascular gene delivery. Gene Ther 7:2023–2027
Wells DJ (2004) Gene therapy progress and prospects: electroporation and other physical methods. Gene Ther 11:1363–1369
Wolff JA, Williams P, Acsadi G et al (1991) Conditions affecting direct gene transfer into rodent muscle in vivo. Biotechniques 11: 474–485
Liu F, Song Y, Liu D (1999) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther 6: 1258–1266
Zhang G, Budker V, Wolff JA (1999) High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 10:1735–1737
Budker V, Zhang G, Danko I et al (1998) The efficient expression of intravascularly delivered DNA in rat muscle. Gene Ther 5:272–276
Zhang G, Gao X, Song YK et al (2004) Hydroporation as the mechanism of hydrodynamic delivery. Gene Ther 11:675–682
Mahato RI, Takakura Y, Hashida M (1997) Nonviral vectors for in vivo gene delivery: physicochemical and pharmacokinetic considerations. Crit Rev Ther Drug Carrier Syst 14:133–172
Mahato RI, Kawabata K, Nomura T et al (1995) Physicochemical and pharmacokinetic characteristics of plasmid DNA/cationic liposome complexes. J Pharm Sci 84:1267–1271
Felgner PL, Gadek TR, Holm M et al (1987) Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci U S A 84:7413–7417
Liu D, Ren T, Gao X (2003) Cationic transfection lipids. Curr Med Chem 10:1307–1315
Li S, Huang L (2000) Nonviral gene therapy: promises and challenges. Gene Ther 7:31–34
Hemmi H, Takeuchi O, Kawai T et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745
Ito Y, Kawakami S, Charoensit P et al (2009) Evaluation of proinflammatory cytokine production and liver injury induced by plasmid DNA/cationic liposome complexes with various mixing ratios in mice. Eur J Pharm Biopharm 71:303–309
Niidome T, Huang L (2002) Gene therapy progress and prospects: nonviral vectors. Gene Ther 9:1647–1652
Brunner S, Furtbauer E, Sauer T et al (2002) Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation. Mol Ther 5: 80–86
Kawakami S, Ito Y, Charoensit P et al (2006) Evaluation of proinflammatory cytokine production induced by linear and branched polyethylenimine/plasmid DNA complexes in mice. J Pharmacol Exp Ther 317:1382–1390
Boussif O, Lezoualc’h F, Zanta MA et al (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci U S A 92:7297–7301
Hackett PB, Podetz-Petersen KM, Bell JB et al (2010) Gene expression in lung and liver after intravenous infusion of polyethyleneimine complexes and hydrodynamic delivery of sleeping beauty transposons. Hum Gene Ther 21(2): 210–20
Oh YK, Kim JP, Yoon H et al (2001) Prolonged organ retention and safety of plasmid DNA administered in polyethylenimine complexes. Gene Ther 8:1587–1592
Guo ZS, Wang LH, Eisensmith RC et al (1996) Evaluation of promoter strength for hepatic gene expression in vivo following adenovirus-mediated gene transfer. Gene Ther 3:802–810
Boshart M, Weber F, Jahn G et al (1985) A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell 41:521–530
Zhang XY, Ni YS, Saifudeen Z et al (1995) Increasing binding of a transcription factor immediately downstream of the cap site of a cytomegalovirus gene represses expression. Nucleic Acids Res 23:3026–3033
Sinclair JH, Baillie J, Bryant LA et al (1992) Repression of human cytomegalovirus major immediate early gene expression in a monocytic cell line. J Gen Virol 73(Pt 2):433–435
Gill DR, Smyth SE, Goddard CA et al (2001) Increased persistence of lung gene expression using plasmids containing the ubiquitin C or elongation factor 1alpha promoter. Gene Ther 8:1539–1546
Schorpp M, Jager R, Schellander K et al (1996) The human ubiquitin C promoter directs high ubiquitous expression of transgenes in mice. Nucleic Acids Res 24:1787–1788
Yew NS, Przybylska M, Ziegler RJ et al (2001) High and sustained transgene expression in vivo from plasmid vectors containing a hybrid ubiquitin promoter. Mol Ther 4:75–82
Cullen BR (2003) Nuclear RNA export. J Cell Sci 116:587–597
Buchman AR, Berg P (1988) Comparison of intron-dependent and intron-independent gene expression. Mol Cell Biol 8:4395–4405
Huang J, Liang TJ (1993) A novel hepatitis B virus (HBV) genetic element with Rev response element-like properties that is essential for expression of HBV gene products. Mol Cell Biol 13:7476–7486
Donello JE, Loeb JE, Hope TJ (1998) Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element. J Virol 72:5085–5092
Krieg AM (2000) The role of CpG motifs in innate immunity. Curr Opin Immunol 12:35–43
Chen ZY, Riu E, He CY et al (2008) Silencing of episomal transgene expression in liver by plasmid bacterial backbone DNA is independent of CpG methylation. Mol Ther 16: 548–556
Yew NS, Wang KX, Przybylska M et al (1999) Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid: pDNA complexes. Hum Gene Ther 10: 223–234
Argyros O, Wong SP, Fedonidis C et al (2011) Development of S/MAR minicircles for enhanced and persistent transgene expression in the mouse liver. J Mol Med 89:515–29
Gill D, Pringle I, Hyde SC (2009) Progress and prospects: the design and production of plasmid vectors. Gene Ther 16:165–171
Wong SP, Argyros O, Coutelle C et al (2009) Strategies for the episomal modification of cells. Curr Opin Mol Ther 11:433–441
Rothenfusser S, Tuma E, Wagner M et al (2003) Recent advances in immunostimulatory CpG oligonucleotides. Curr Opin Mol Ther 5: 98–106
Jackson DA, Cook PR (1995) The structural basis of nuclear function. Int Rev Cytol 162A: 125–149
Piechaczek C, Fetzer C, Baiker A et al (1999) A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells. Nucleic Acids Res 27:426–428
Jenke AC, Scinteie MF, Stehle IM et al (2004) Expression of a transgene encoded on a non-viral episomal vector is not subject to epigenetic silencing by cytosine methylation. Mol Biol Rep 31:85–90
Jenke BH, Fetzer CP, Stehle IM et al (2002) An episomally replicating vector binds to the nuclear matrix protein SAF-A in vivo. EMBO Rep 3:349–354
Papapetrou EP, Ziros PG, Micheva ID et al (2006) Gene transfer into human hematopoietic progenitor cells with an episomal vector carrying an S/MAR element. Gene Ther 13: 40–51
Girod PA, Nguyen DQ, Calabrese D et al (2007) Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat Methods 4: 747–753
Stief A, Winter DM, Stratling WH et al (1989) A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature 341:343–345
Klehr D, Schlake T, Maass K et al (1992) Scaffold-attached regions (SAR elements) mediate transcriptional effects due to butyrate. Biochemistry 31:3222–3229
Bonifer C, Vidal M, Grosveld F et al (1990) Tissue specific and position independent expression of the complete gene domain for chicken lysozyme in transgenic mice. EMBO J 9:2843–2848
McKnight RA, Shamay A, Sankaran L et al (1992) Matrix-attachment regions can impart position-independent regulation of a tissue-specific gene in transgenic mice. Proc Natl Acad Sci U S A 89:6943–6947
Lichtenstein M, Keini G, Cedar H et al (1994) B cell-specific demethylation: a novel role for the intronic kappa chain enhancer sequence. Cell 76:913–923
Forrester WC, Fernandez LA, Grosschedl R (1999) Nuclear matrix attachment regions antagonize methylation-dependent repression of long-range enhancer-promoter interactions. Genes Dev 13:3003–3014
Girod PA, Mermod N (2003) Use of scaffold/matrix-attachment regions for protein production. Elsevier Science B.V. Makrides SC (Ed.) Gene Transfer and Expression in Mammalian Cells, Chapter 10
Kalos M, Fournier R (1995) Position-independant transgene expression mediated by boundary elements from the apoliprotein B chromatin domain. Mol Cell Biol 15:198–207
Ottaviani D, Lever E, Takousis P et al (2008) Anchoring the genome. Genome Biol 9:201
Harraghy N, Gaussin A, Mermod N (2008) Sustained transgene expression using MAR elements. Curr Gene Ther 8:353–366
Mielke C, Kohwi Y, Kohwi-Shigematsu T et al (1990) Hierarchical binding of DNA fragments derived from scaffold-attached regions: correlation of properties in vitro and function in vivo. Biochemistry 29:7475–7485
Allen GC, Hall G Jr, Michalowski S et al (1996) High-level transgene expression in plant cells: effects of a strong scaffold attachment region from tobacco. Plant Cell 8:899–913
Stehle IM, Postberg J, Rupprecht S et al (2007) Establishment and mitotic stability of an extra-chromosomal mammalian replicon. BMC Cell Biol 8:33
Bigger BW, Tolmachov O, Collombet JM et al (2001) An araC-controlled bacterial cre expression system to produce DNA minicircle vectors for nuclear and mitochondrial gene therapy. J Biol Chem 276:23018–23027
Chen ZY, He CY, Ehrhardt A et al (2003) Minicircle DNA vectors devoid of bacterial DNA result in persistent and high-level transgene expression in vivo. Mol Ther 8:495–500
Darquet AM, Rangara R, Kreiss P et al (1999) Minicircle: an improved DNA molecule for in vitro and in vivo gene transfer. Gene Ther 6: 209–218
Nehlsen K, Broll S, Bode J (2006) Replicating minicircles: generation of nonviral episomes for the efficient modification of dividing cells. Gene Ther Mol Biol 10:233–244
Riu E, Chen ZY, Xu H et al (2007) Histone modifications are associated with the persistence or silencing of vector-mediated transgene expression in vivo. Mol Ther 15:1348–1355
Vaysse L, Gregory LG, Harbottle RP et al (2006) Nuclear-targeted minicircle to enhance gene transfer with non-viral vectors in vitro and in vivo. J Gene Med 8:754–763
Zhang X, Epperly MW, Kay MA et al (2008) Radioprotection in vitro and in vivo by minicircle plasmid carrying the human manganese superoxide dismutase transgene. Hum Gene Ther 19:820–826
Chang CW, Christensen LV, Lee M et al (2008) Efficient expression of vascular endothelial growth factor using minicircle DNA for angiogenic gene therapy. J Control Release 125: 155–163
Kim S, Landy A (1992) Lambda Int protein bridges between higher order complexes at two distant chromosomal foci attL and attR. Science 256:198–203
Abremski K, Hoess R (1984) Bacteriophage P1 site-specific recombination. Purification and properties of the Cre recombinase protein. J Biol Chem 259:1509–1514
Sternberg N, Sauer B, Hoess R et al (1986) Bacteriophage P1 cre gene and its regulatory region. Evidence for multiple promoters and for regulation by DNA methylation. J Mol Biol 187:197–212
Thorpe HM, Wilson SE, Smith MC (2000) Control of directionality in the site-specific recombination system of the Streptomyces phage phiC31. Mol Microbiol 38:232–241
Groth AC, Olivares EC, Thyagarajan B et al (2000) A phage integrase directs efficient site-specific integration in human cells. Proc Natl Acad Sci U S A 97:5995–6000
Chen L, Woo SL (2005) Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA. Proc Natl Acad Sci U S A 102:15581–15586
Benzinger R, Enquist LW, Skalka A (1975) Transfection of Escherichia coli spheroplasts. V. Activity of recBC nuclease in rec + and rec minus spheroplasts measured with different forms of bacteriophage DNA. J Virol 15: 861–871
Buchholz F, Ringrose L, Angrand PO et al (1996) Different thermostabilities of FLP and Cre recombinases: implications for applied site-specific recombination. Nucl Acids Res 24: 4256–4262
Mislick KA, Baldeschwieler JD (1996) Evidence for the role of proteoglycans in cation-mediated gene transfer. Proc Natl Acad Sci U S A 93:12349–12354
Gharwan H, Wightman L, Kircheis R et al (2003) Nonviral gene transfer into fetal mouse livers (a comparison between the cationic polymer PEI and naked DNA). Gene Ther 10: 810–817
Pollard H, Remy JS, Loussouarn G et al (1998) Polyethylenimine but not cationic lipids promotes transgene delivery to the nucleus in mammalian cells. J Biol Chem 273: 7507–7511
Wong SP, Argyros O, Howe SJ et al (2010) Systemic gene transfer of polyethylenimine (PEI)-plasmid DNA complexes to neonatal mice. J Control Release 150:298–306
Felt O, Buri P, Gurny R (1998) Chitosan: a unique polysaccharide for drug delivery. Drug Dev Ind Pharm 24:979–993
Tabata H, Nakajima K (2001) Efficient in utero gene transfer system to the developing mouse brain using electroporation: visualization of neuronal migration in the developing cortex. Neuroscience 103:865–872
Saito T, Nakatsuji N (2001) Efficient gene transfer into the embryonic mouse brain using in vivo electroporation. Dev Biol 240:237–246
Sato M, Tanigawa M, Kikuchi N (2004) Nonviral gene transfer to surface skin of mid-gestational murine embryos by intraamniotic injection and subsequent electroporation. Mol Reprod Dev 69:268–277
Garcia-Frigola C, Carreres MI, Vegar C et al (2007) Gene delivery into mouse retinal ganglion cells by in utero electroporation. BMC Dev Biol 7:103
Kay MA, He CY, Chen ZY (2010) A robust system for production of minicircle DNA vectors. Nat Biotechnol 28:1287–1289
Koping-Hoggard M, Tubulekas I, Guan H et al (2001) Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo. Gene Ther 8:1108–1121
Yang PT, Hoang L, Jia WW et al (2011) In utero gene delivery using Chitosan-DNA nanoparticles in mice. J Surg Res 171(2):691–9
Sase M, Miwa I, Sumie M et al (2005) Gastric emptying cycles in the human fetus. Am J Obstet Gynecol 193:1000–1004
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Wong, S.P., Argyros, O., Harbottle, R.P. (2012). Vector Systems for Prenatal Gene Therapy: Principles of Non-viral Vector Design and Production. In: Coutelle, C., Waddington, S. (eds) Prenatal Gene Therapy. Methods in Molecular Biology, vol 891. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-873-3_7
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