Enhancement of MSH receptor- and GAL4-mediated gene transfer by switching the nuclear import pathway

Gene Therapy
C K Chan, David A Jans

Abstract

Efficient nuclear delivery of plasmid DNA represents a major barrier in nonviral gene transfer. One approach has been to use DNA-binding proteins such as GAL4 from yeast as DNA carriers with nuclear targeting properties. We recently showed, however, that GAL4 is inefficient in targeting DNA to the nucleus because its DNA-binding and nuclear targeting activities are mutually exclusive, which relates to the fact that GAL4 nuclear import occurs via a novel pathway. Here, we 'switch' this pathway to a more conventional one by adding a modified poly-lysine to which an optimized nuclear targeting signal, based on that of the SV40 large T-antigen, is linked. We also use a chimeric GAL4-alpha-melanocyte stimulating hormone (MSH) fusion protein to enable gene transfer to cells expressing the MSH receptor. Switching the nuclear import pathway of the transfecting complex significantly enhances receptor-mediated gene transfer through enabling interaction with desired components of the cellular nuclear import machinery. The present study represents the first demonstration that nuclear targeting signals can enhance receptor-mediated gene delivery, the approaches having important relevance to research and clinical applications, such as in gen...Continue Reading

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Citations

Jun 6, 2003·Advanced Drug Delivery Reviews·Felix M MunkongeEric W F W Alton
Mar 12, 2005·Nature Reviews. Genetics·Dominic J GloverDavid A Jans
May 24, 2005·Gene Therapy·D A DeanW E Zimmer
Mar 1, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kylie M WagstaffDavid A Jans
Apr 10, 2002·Immunology and Cell Biology·Chee-Kai Chan, David A Jans
Feb 20, 2008·Biochemistry. Biokhimii︠a︡·A V SorokinL P Ovchinnikov
Jan 28, 2014·Biochemistry. Biokhimii︠a︡·A A RosenkranzA S Sobolev
Oct 26, 2010·Journal of Controlled Release : Official Journal of the Controlled Release Society·Geertrui TavernierJoanna Rejman
Apr 28, 2009·Advanced Drug Delivery Reviews·Aaron M Miller, David A Dean
Jun 9, 2005·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·U LungwitzA Göpferich
Aug 5, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Mikhail O DurymanovAlexander S Sobolev
Sep 3, 2013·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jacob J ElmerKaushal Rege
Apr 20, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Gualtiero AlvisiDavid A Jans
Jun 21, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dean A JacksonHans J Lipps
Dec 31, 2008·Chembiochem : a European Journal of Chemical Biology·Fozia NoorNils Metzler-Nolte
Mar 22, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kylie M WagstaffDavid A Jans
Nov 11, 2003·The Journal of Biological Chemistry·Laurence VaysseCharles Coutelle
Aug 8, 2007·The Biochemical Journal·Kylie M Wagstaff, David A Jans
Apr 15, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Andrey A RosenkranzAlexander S Sobolev

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