Abstract
An efficient and safe method to deliver DNA in vivo is a requirement for several purposes, such as the study of gene function and gene therapy applications. Among the different nonviral delivery methods currently under investigation, in vivo DNA electrotransfer has proven to be one of the most efficient and simple methods. This technique is a physical method of gene delivery consisting of a local application of electric pulses after injection of DNA.
This technique can be applied to almost any tissue of a living animal, including tumors, skin, liver, kidney, artery, retina, cornea, or even brain, but the focus of this review will be on electrotransfer of plasmid DNA into skeletal muscle and its possible therapeutic uses for systemic diseases. Skeletal muscle is a good target for electrotransfer of DNA because of the following features: a large volume of easily accessible tissue, an endocrine organ capable of expressing several local and systemic factors, and muscle fibers as postmitotic cells have a long lifespan, which allows long-term gene expression.
In this review, we will describe the main characteristics of DNA electrotransfer, including toxicity and safety issues related to this technique. We will focus on the important possible therapeutic applications of electrotransfer for systemic diseases demonstrated in animal models in the recent years, in the fields of monogenic diseases, tissue-specific diseases, metabolic disorders, immune-system-related diseases, and cancer. Finally, we will discuss the advantages and challenges of this technique.
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References
1. Neumann, E., Schaefer-Ridder, M., Wang, Y., and Hofschneider, P.H. (1982) Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J. 1, 841–845.
2. Belehradek, J., Jr., Orlowski, S., Ramirez, L.H., Pron, G., Poddevin, B., and Mir, L.M. (1994) Electropermeabilization of cells in tissues assessed by the qualitative and quantitative electroloading of bleomycin. Biochim. Biophys. Acta. 1190, 155–163.
3. Mir, L.M. and Orlowski, S. (1999) Mechanisms of electrochemotherapy. Adv. Drug Deliv. Rev. 35, 107–118.
4. Sersa, G., Stabuc, B., Cemazar, M., Miklavcic, D., and Rudolf, Z. (2000) Electrochemotherapy with cisplatin: the systemic antitumour effectiveness of cisplatin can be potentiated locally by the application of electric pulses in the treatment of malignant melanoma skin metastases. Melanoma Res. 10, 381–385.
5. Rebersek, M., Cufer, T., Cemazar, M., Kranjc, S., and Sersa, G. (2004) Electrochemotherapy with cisplatin of cutaneous tumor lesions in breast cancer. Anticancer Drugs. 15, 593–597.
6. Rols, M.P., Tamzali, Y., and Teissie, J. (2002) Electrochemotherapy of horses. A preliminary clinical report. Bioelectrochemistry. 55, 101–105.
7. Heller, L.C., Ugen, K., and Heller, R. (2005) Electroporation for targeted gene transfer. Expert Opin. Drug Deliv. 2, 255–268.
8. Li, S. (2004) Electroporation gene therapy: new developments in vivo and in vitro. Curr. Gene Ther. 4, 309–316.
Trollet, C., Bigey, P., and Scherman, D. (2005) Electrotransfection: an overview. In: Schleef, M. (ed.). DNA-pharmaceuticals. Wiley-VCH, Weinheim, Chap. 11, pp. 189–218.
10. Prud'homme, G.J., Glinka, Y., Khan, A.S., and Draghia-Akli, R. (2006) Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Curr. Gene Ther. 6, 243–273.
11. Faurie, C., Phez, E., Golzio, M., et al. (2004) Effect of electric field vectoriality on electrically mediated gene delivery in mammalian cells. Biochim. Biophys. Acta. 1665, 92–100.
12. Mir, L.M., Bureau, M.F., Rangara, R., Schwartz, B., and Scherman, D. (1998) Long-term, high level in vivo gene expression after electric pulse-mediated gene transfer into skeletal muscle. C.R. Acad. Sci. III. 321, 893–899.
13. Vicat, J.M., Boisseau, S., Jourdes, P., et al. (2000) Muscle transfection by electroporation with high-voltage and short-pulse currents provides high-level and long-lasting gene expression. Hum. Gene Ther. 11, 909–916.
14. Mir, L.M., Moller, P.H., Andre, F., and Gehl, J. (2005) Electric pulse-mediated gene delivery to various animal tissues. Adv. Genet. 54, 83–114.
15. Mir, L.M., Bureau, M.F., Gehl, J., et al. (1999) High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc. Natl. Acad. Sci. U.S.A. 96, 4262–4267.
16. Lu, Q.L., Bou-Gharios, G., and Partridge, T.A. (2003) Non-viral gene delivery in skeletal muscle: a protein factory. Gene Ther. 10, 131–142.
17. Goldspink, G. (2003) Skeletal muscle as an artificial endocrine tissue. Best Pract. Res. Clin. Endocrinol. Metab. 17, 211–222.
18. Trollet, C., Ibanez-Ruiz, M., Bloquel, C., Valin, G., Scherman, D., and Bigey, P. (2004) Regulation of gene expression using a conditional RNA antisense strategy. J. Genome Sci. Tech. 3, 1–13.
19. Bettan, M., Emmanuel, F., Darteil, R., et al. (2000) High-level protein secretion into blood circulation after electric pulse-mediated gene transfer into skeletal muscle. Mol. Ther. 2, 204–210.
20. Kreiss, P., Bettan, M., Crouzet, J., and Scherman, D. (1999) Erythropoietin secretion and physiological effect in mouse after intramuscular plasmid DNA electrotransfer. J. Gene Med. 1, 245–250.
21. Honigman, A., Zeira, E., Ohana, P., et al. (2001) Imaging transgene expression in live animals. Mol. Ther. 4, 239–249.
22. Peng, B., Zhao, Y., Lu, H., Pang, W., and Xu, Y. (2005) In vivo plasmid DNA electroporation resulted in transfection of satellite cells and lasting transgene expression in regenerated muscle fibers. Biochem. Biophys. Res. Commun. 338, 1490–1498.
23. Gehl, J. and Mir, L.M. (1999) Determination of optimal parameters for in vivo gene transfer by electroporation, using a rapid in vivo test for cell permeabilization. Biochem. Biophys. Res. Commun. 261, 377–380.
24. Mathiesen, I. (1999) Electropermeabilization of skeletal muscle enhances gene transfer in vivo. Gene Ther. 6, 508–514.
25. Leroy-Willig, A., Bureau, M.F., Scherman, D., and Carlier, P.G. (2005) In vivo NMR imaging evaluation of efficiency and toxicity of gene electrotransfer in rat muscle. Gene Ther. 12, 1434–1443.
26. Hartikka, J., Sukhu, L., Buchner, C., et al. (2001) Electroporation-facilitated delivery of plasmid DNA in skeletal muscle: plasmid dependence of muscle damage and effect of poloxamer 188. Mol. Ther. 4, 407–415.
27. Durieux, A.C., Bonnefoy, R., Busso, T., and Freyssenet, D. (2004) In vivo gene electrotransfer into skeletal muscle: effects of plasmid DNA on the occurrence and extent of muscle damage. J. Gene Med. 6, 809–816.
28. Bertrand, A., Ngo-Muller, V., Hentzen, D., Concordet, J.P., Daegelen, D., and Tuil, D. (2003) Muscle electrotransfer as a tool for studying muscle fiber-specific and nerve-dependent activity of promoters. Am. J. Physiol. Cell Physiol. 285, C1071–C1081.
29. Davis, H.L., Whalen, R.G., and Demeneix, B.A. (1993) Direct gene transfer into skeletal muscle in vivo: factors affecting efficiency of transfer and stability of expression. Hum. Gene Ther. 4, 151–159.
30. Mennuni, C., Calvaruso, F., Zampaglione, I., et al. (2002) Hyaluronidase increases electrogene transfer efficiency in skeletal muscle. Hum. Gene Ther. 13, 355–365.
31. Favre, D., Cherel, Y., Provost, N., et al. (2000) Hyaluronidase enhances recombinant adeno-associated virus (rAAV)-mediated gene transfer in the rat skeletal muscle. Gene Ther. 7, 1417–1420.
32. McMahon, J.M., Signori, E., Wells, K.E., Fazio, V.M., and Wells, D.J. (2001) Optimisation of electrotransfer of plasmid into skeletal muscle by pretreatment with hyaluronidase—increased expression with reduced muscle damage. Gene Ther. 8, 1264–1270.
33. Molnar, M.J., Gilbert, R., Lu, Y., et al. (2004) Factors influencing the efficacy, longevity, and safety of electroporation-assisted plasmid-based gene transfer into mouse muscles. Mol. Ther. 10, 447–455.
34. Ferrer, A., Foster, H., Wells, K.E., et al. (2004) Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins. Gene Ther. 11, 884–893.
35. Fewell, J.G., MacLaughlin, F., Mehta, V., et al. (2001) Gene therapy for the treatment of hemophilia B using PINC-formulated plasmid delivered to muscle with electroporation. Mol. Ther. 3, 574–583.
36. Arruda, V.R., Hagstrom, J.N., Deitch, J., et al. (2001) Posttranslational modifications of recombinant myotube-synthesized human factor IX. Blood. 97, 130–138.
37. Long, Y.C., Jaichandran, S., Ho, L.P., Tien, S.L., Tan, S.Y., and Kon, O.L. (2005) FVIII gene delivery by muscle electroporation corrects murine hemophilia A. J. Gene Med. 7, 494–505.
38. Mei, W.H., Qian, G.Q., Zhang, X.Q., Zhang, P., and Lu, J. (2006) Sustained expression of Epstein-Barr virus episomal vector mediated factor VIII in vivo following muscle electroporation. Haemophilia. 12, 271–279.
39. Maruyama, H., Sugawa, M., Moriguchi, Y., et al. (2000) Continuous erythropoietin delivery by muscle-targeted gene transfer using in vivo electroporation. Hum. Gene Ther. 11, 429–437.
40. Payen, E., Bettan, M., Rouyer-Fessard, P., Beuzard, Y., and Scherman, D. (2001) Improvement of mouse beta-thalassemia by electrotransfer of erythropoietin cDNA. Exp. Hematol. 29, 295–300.
41. Maruyama, H., Ataka, K., Gejyo, F., et al. (2001) Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats. Gene Ther. 8, 461–468.
42. Dalle, B., Henri, A., Rouyer-Fessard, P., et al. (2001) Dimeric erythropoietin fusion protein with enhanced erythropoietic activity in vitro and in vivo. Blood. 97, 3776–3782.
43. Rizzuto, G., Cappelletti, M., Maione, D., et al. (1999) Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation. Proc. Natl. Acad. Sci. U.S.A. 96, 6417–6422.
44. Fattori, E., Cappelletti, M., Zampaglione, I., et al. (2005) Gene electro-transfer of an improved erythropoietin plasmid in mice and non-human primates. J. Gene Med. 7, 228–236.
45. Komamura, K., Tatsumi, R., Miyazaki, J., et al. (2004) Treatment of dilated cardiomyopathy with electroporation of hepatocyte growth factor gene into skeletal muscle. Hypertension. 44, 365–371.
46. Umeda, Y., Marui, T., Matsuno, Y., et al. (2004) Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice. Lab. Invest. 84, 836–844.
47. Pradat, P.F., Kennel, P., Naimi-Sadaoui, S., et al. (2002) Viral and non-viral gene therapy partially prevents experimental cisplatin-induced neuropathy. Gene Ther. 9, 1333–1337.
48. Lesbordes, J.C., Bordet, T., Haase, G., et al. (2002) In vivo electrotransfer of the cardiotrophin-1 gene into skeletal muscle slows down progression of motor neuron degeneration in pmn mice. Hum. Mol. Genet. 11, 1615–1625.
49. Ataka, K., Maruyama, H., Neichi, T., Miyazaki, J., and Gejyo, F. (2003) Effects of erythropoietin-gene electrotransfer in rats with adenine-induced renal failure. Am. J. Nephrol. 23, 315–323.
50. Rizzuto, G., Cappelletti, M., Mennuni, C., et al. (2000) Gene electrotransfer results in a high-level transduction of rat skeletal muscle and corrects anemia of renal failure. Hum. Gene Ther. 11, 1891–1900.
51. Draghia-Akli, R., Ellis, K.M., Hill, L.A., Malone, P.B., and Fiorotto, M.L. (2003) High-efficiency growth hormone-releasing hormone plasmid vector administration into skeletal muscle mediated by electroporation in pigs. FASEB J. 17, 526–528.
52. Draghia-Akli, R. and Fiorotto, M.L. (2004) A new plasmid-mediated approach to supplement somatotropin production in pigs. J. Anim. Sci. 82 (E-Suppl.), E264–E269.
53. Xiang, L., Murai, A., Sugahara, K., Yasui, A., and Muramatsu, T. (2003) Effects of leptin gene expression in mice in vivo by electroporation and hydrodynamics-based gene delivery. Biochem. Biophys. Res. Commun. 307, 440–445.
54. Mallat, Z., Silvestre, J.S., Le Ricousse-Roussanne, S., et al. (2002) Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. Circ. Res. 91, 441–448.
55. Silvestre, J.S., Mallat, Z., Duriez, M., et al. (2000) Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb. Circ. Res. 87, 448–452.
56. Nishikage, S., Koyama, H., Miyata, T., Ishii, S., Hamada, H., and Shigematsu, H. (2004) In vivo electroporation enhances plasmid-based gene transfer of basic fibroblast growth factor for the treatment of ischemic limb. J. Surg. Res. 120, 37–46.
57. Sugano, M., Hata, T., Tsuchida, K., et al. (2004) Local delivery of soluble TNF-alpha receptor 1 gene reduces infarct size following ischemia/reperfusion injury in rats. Mol. Cell Biochem. 266, 127–132.
58. Silvestre, J.S., Tamarat, R., Ebrahimian, T.G., et al. (2003) Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circ. Res. 93, 114–123.
59. Kon, O.L., Sivakumar, S., Teoh, K.L., Lok, S.H., and Long, Y.C. (1999) Naked plasmid-mediated gene transfer to skeletal muscle ameliorates diabetes mellitus. J. Gene Med. 1, 186–194.
60. Martinenghi, S., Cusella De Angelis, G., Biressi, S., et al. (2002) Human insulin production and amelioration of diabetes in mice by electrotransfer-enhanced plasmid DNA gene transfer to the skeletal muscle. Gene Ther. 9, 1429–1437.
61. Croze, F. and Prud'homme, G.J. (2003) Gene therapy of streptozotocin-induced diabetes by intramuscular delivery of modified preproinsulin genes. J. Gene Med. 5, 425–437.
62. Sun, W., Wang, L., Zhang, Z., Chen, M., and Wang, X. (2003) Intramuscular transfer of naked calcitonin gene-related peptide gene prevents autoimmune diabetes induced by multiple low-dose streptozotocin in C57BL mice. Eur. J. Immunol. 33, 233–242.
63. Tavakoli, R., Gazdhar, A., Pierog, J., et al. (2006) Electroporation-mediated interleukin-10 overexpression in skeletal muscle reduces acute rejection in rat cardiac allografts. J. Gene Med. 8, 242–248.
64. Nakano, A., Matsumori, A., Kawamoto, S., et al. (2001) Cytokine gene therapy for myocarditis by in vivo electroporation. Hum. Gene Ther. 12, 1289–1297.
65. Watanabe, K., Nakazawa, M., Fuse, K., et al. (2001) Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation. Circulation. 104, 1098–1100.
66. Adachi, O., Nakano, A., Sato, O., et al. (2002) Gene transfer of Fc-fusion cytokine by in vivo electroporation: application to gene therapy for viral myocarditis. Gene Ther. 9, 577–583.
67. Jiang, J., Yamato, E., and Miyazaki, J. (2003) Sustained expression of Fc-fusion cytokine following in vivo electroporation and mouse strain differences in expression levels. J. Biochem. (Tokyo). 133, 423–427.
68. Mallat, Z., Besnard, S., Duriez, M., et al. (1999) Protective role of interleukin-10 in atherosclerosis. Circ. Res. 85, e17–e24.
69. Mallat, Z., Corbaz, A., Scoazec, A., et al. (2001) Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41–E45.
70. Hase, M., Tanaka, M., Yokota, M., and Yamada, Y. (2002) Reduction in the extent of atherosclerosis in apolipoprotein E-deficient mice induced by electroporation-mediated transfer of the human plasma platelet-activating factor acetylhydrolase gene into skeletal muscle. Prostaglandins Other Lipid Mediat. 70, 107–118.
71. Saidenberg-Kermanac'h, N., Bessis, N., Deleuze, V., et al. (2003) Efficacy of interleukin-10 gene electrotransfer into skeletal muscle in mice with collagen-induced arthritis. J. Gene Med. 5, 164–171.
72. Ho, S.H., Hahn, W., Lee, H.J., et al. (2004) Protection against collagen-induced arthritis by electrotransfer of an expression plasmid for the interleukin-4. Biochem. Biophys. Res. Commun. 321, 759–766.
73. Jeong, J.G., Kim, J.M., Ho, S.H., Hahn, W., Yu, S.S., and Kim, S. (2004) Electrotransfer of human IL-1Ra into skeletal muscles reduces the incidence of murine collagen-induced arthritis. J. Gene Med. 6, 1125–1133.
74. Olsen, N.J. and Stein, C.M. (2004) New drugs for rheumatoid arthritis. N. Engl. J. Med. 350, 2167–2179.
75. Bloquel, C., Bessis, N., Boissier, M.C., Scherman, D., and Bigey, P. (2004) Gene therapy of collagen-induced arthritis by electrotransfer of human tumor necrosis factor-alpha soluble receptor I variants. Hum. Gene Ther. 15, 189–201.
76. Kim, J.M., Ho, S.H., Hahn, W., et al. (2003) Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein. Gene Ther. 10, 1216–1224.
77. Bloquel, C., Bejjani, R., Bigey, P., et al. (2006) Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF-alpha soluble receptor in uveitis. FASEB J. 20, 389–391.
78. Lucas, M.L. and Heller, R. (2001) Immunomodulation by electrically enhanced delivery of plasmid DNA encoding IL-12 to murine skeletal muscle. Mol. Ther. 3, 47–53.
79. Lee, S.C., Wu, C.J., Wu, P.Y., Huang, Y.L., Wu, C.W., and Tao, M.H. (2003) Inhibition of established subcutaneous and metastatic murine tumors by intramuscular electroporation of the interleukin-12 gene. J. Biomed. Sci. 10, 73–86.
80. Li, S., Zhang, L., Torrero, M., Cannon, M., and Barret, R. (2005) Administration route- and immune cell activation-dependent tumor eradication by IL12 electrotransfer. Mol. Ther. 12, 942–949.
81. Li, S., Zhang, X., Xia, X. et al. (2001) Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site. Gene Ther. 8, 400–407.
82. Zhang, G.H., Tan, X.F., Shen, D., et al. (2003) Gene expression and antitumor effect following im electroporation delivery of human interferon alpha 2 gene. Acta. Pharmacol. Sin. 24, 891–896.
83. Celiker, M.Y., Wang, M., Atsidaftos, E., et al. (2001) Inhibition of Wilms' tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA. Oncogene. 20, 4337–4343.
84. Cichon, T., Jamrozy, L., Glogowska, J., Missol-Kolka, E., and Szala, S. (2002) Electrotransfer of gene encoding endostatin into normal and neoplastic mouse tissues: inhibition of primary tumor growth and metastatic spread. Cancer Gene Ther. 9, 771–777.
85. Bossard, C., Van den Berghe, L., Laurell, H., et al. (2004) Antiangiogenic properties of fibstatin, an extracellular FGF-2-binding polypeptide. Cancer Res. 64, 7507–7512.
86. Ivanov, M.A., Lamrihi, B., Szyf, M., Scherman, D., and Bigey, P. (2003) Enhanced antitumor activity of a combination of MBD2-antisense electrotransfer gene therapy and bleomycin electrochemotherapy. J. Gene Med. 5, 893–899.
87. Pelegrin, M., Gros, L., Dreja, H., and Piechaczyk, M. (2004) Monoclonal antibody-based genetic immunotherapy. Curr. Gene Ther. 4, 347–356.
88. Perez, N., Bigey, P., Scherman, D., Danos, O., Piechaczyk, M., and Pelegrin, M. (2004) Regulatable systemic production of monoclonal antibodies by in vivo muscle electroporation. Genet. Vaccines Ther. 2, 2.
Christian H. Ottensmeier et al. (2006) 4th international workshop on DNA vaccines, Trest. Complete information about this clinical trial can be found on the Internet site: http://www.inovio.com/
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Trollet, C., Scherman, D., Bigey, P. (2008). Delivery of DNA into Muscle for Treating Systemic Diseases: Advantages and Challenges. In: Li, S. (eds) Electroporation Protocols. Methods in Molecular Biology™, vol 423. Humana Press. https://doi.org/10.1007/978-1-59745-194-9_14
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