THE USE OF FUSOGENIC LIPIDS AND HDAC6 INHIBITORS TO ENHANCE GENE DELIVERY

Abstract

There are growing studies with evidence that ex vivo genetic modifications of human cells, improve therapeutic potentials. Conventional viral vectors are favourable, but hindered by large-scale production issues. Currently, lentivirus production relies on transient transfection which are poor and inconsistent. Previously, the barriers to transient transfection of hard-to-transfect cells was systematically identified and eventually mitigated with the use of DOPE/CHEMS and HDAC6 inhibitors in a cationic-polymer based transfection workflow. As an extension, multiple-plasmid transfection was shown to be similarly enhanced, translating to higher lentivirus production. DOPE/CHEMS and SAHA also significantly enhanced transduction of hard-to-transduce cells. Another emerging therapy is the delivery of therapeutic proteins with genetically-modified cellular vehicles like MSC, which are poorly and inconsistently transfected. In our UC-MSC model, DOPE/CHEMS and HDAC6 inhibitors enhanced MSC transfection, resulting in increased functional protein release. Overall, these studies provide novel findings and is translatable to a wide range of applications.