776. A Novel Dual Functioning Non-Viral Vector - Delivering Genes While Targeting Nuclear Receptor Signaling

Abstract

Non-viral vectors, for example cationic liposomes, have been widely used for in vivo and in vitro gene delivery. These vectors carry DNA through charge interactions into cells. The DNA, upon trafficking into a cell, will release in the cytoplasm and cross the nuclear membrane to gain access to the cellular transcriptional machinery. Currently, most efforts to design a new viral vector focus on only efficiently delivering DNA into cells, which lack an important function regulating nuclei transcription. Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of nuclei transcriptional regulations. Therefore, a new generation of non-viral vectors should exhibit dual functions, which deliver not only xenogenic transgenes but also some candidate ligands targeting nuclear receptor signaling. Accordingly, the ligands delivered can trigger the nuclear receptor signaling that activates the transgene expression, or inactivates a target gene by co-delivery of inhibitors. In this study, we developed a dual function-vector by encapsulating CDCA (chenodexyxholic acid) as a ligand to target the nuclear receptor, farnesoid X receptor (FXR). FXR has been shown to be an essential regulator of bile acid and lipid metabolism. When CDCA binds to FXR, FXR forms a homodimer with the liver X receptor (LXR). Binding of the homodimer to FXR response element (FXRRE) trances chemical signals into transcriptional machinery of target genes which involve in various physiological processes.