Development of Target-specific Gene Therapy System by Controlling Distribution of Interferon

Interferon-gamma (IFN-gamma) is a type II IFN that possesses various biological activities including antivirus effect and antitumor effect. Because of its potent biological activities, IFN-gamma has been used as a therapeutic treatment for cancer patients and is expected to be a therapeutic for other diseases. As the half-life of IFN-gamma in blood circulation is very short, IFN-gamma gene therapy, in which IFN-gamma gene is used to continuously supply IFN-gamma protein, is a promising approach because it can continuously supply IFN-gamma. To improve therapeutic effect of IFN-gamma-based gene therapy, it is important to control the spatiotemporal distribution of IFN-gamma expressed from the plasmid DNA vector encoding IFN-gamma. We developed a method to regulate the time profile of IFN-gamma expressed from plasmid DNA by modifying vector backbone. In addition, we developed a method that can increase retention time of IFN-gamma in blood circulation by designing IFN-gamma encoded in plasmid vector as a fusion protein with mouse serum albumin (MSA). Regulation of time profile of IFN-gamma expression was highly effective in avoiding unwanted effect of IFN-gamma without decreasing therapeutic effect. In addition, gene delivery of MSA-IFN-gamma fusion protein increased retention time of IFN-gamma in blood circulation than native IFN-gamma gene delivery did. Thus, designing both plasmid vector and therapeutic protein encoded by the vector is a promising approach to controlling the spatiotemporal distribution of proteins which can increase the therapeutic potency of IFN-gamma-based gene therapy as well as safety of in vivo IFN-gamma gene therapy.