NON-VIRAL GENE THERAPY APPROACH FOR REGENERATIVE RECOVERY OF SKIN WOUNDS IN MAMMALS
A. M. Efremov,1—3 I. V. Duhovlinov,1 E. B. Dizhe,1, 3 S. V. Burov,4, 5
M. V. Leko,4, 5 B. N. Akifiev,1, 3 D. A. Mogilenko,1—3 I. A. Ivanov,1
A. P. Perevozchikov,1—3 S. V. Orlov 1—3, *
1 Pharma Gen Ltd. St. Petersburg, 2 St. Petersburg State University, 3 Institute of Experimental Medicine RAMS,
4 Institute of Macromolecular Compounds RAS, and 5 Diapharm Ltd., St. Petersburg;
* e-mail: serge@iem.sp.ru
The rate and character of skin tissue regeneration after wounds, burns and other traumas depend on the cell
proliferation within damaged area. Acceleration of healing by stimulation of cell proliferation and extracellular
matrix synthesis is one of the most important tasks of modern medicine. There are gene therapy approaches to
wound treatment consisting in the transfer of genes encoding mitogenic growth factors to wound area. The most
important step in the development of gene therapy approaches is the design of gene delivery tools. In spite of
high efficacy of viral vectors, the non-viral means have some preferences (low toxicity, low immunogenity, safety
and the absence of backside effects). Among non-viral gene delivery tools, molecular conjugates are the
most popular because of their efficacy, simplicity, and the capacity to the targeted gene transfer. In the present
work we have developed two molecular conjugates — NLS-TSF7 and NLS-TSF12 consisting of the modified
signal of nuclear localization of T-antigen of SV40 virus (cationic part) and the peptide ligands of mammalian
transferrin receptor (ligand part). These conjugates bind to plasmid DNA with formation of polyelectrolytic
complexes and are capable to deliver plasmid DNA into cells expressing transferrin receptors by receptor-mediated
endocytosis. Transfer of the expression vector of luciferase gene in the complex with molecular conjugate
NLS-TSF7 to murine surface tissues led to about 100 fold increasing of luciferase activity in comparison with
the transfer of free expression vector. Treatment of slash wounds in mice with the complexes of expression vector
of synthetic human gene encoding insulin-like growth factor 1 with molecular conjugates NLS-TSF7 led to
acceleration of healing in comparison with mice treated with free expression vector. The results obtained confirm
the high efficiency of the developed regenerative gene therapy approach for the treatment of damaged skin
tissues in mammals.
Key words: molecular conjugates, gene transfer, regenerative gene therapy, transferrin receptor, insulin-like growth factor 1
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