Antifibrotic Effect of MMP13-encoding Plasmid DNA Delivered Using Polyethylenimine Shielded With Hyaluronic Acid

Abstract

The imbalanced expression of matrix metalloproteinases (MMPs) is associated with liver fibrosis, one of the most common chronic liver diseases. Enhanced expression of MMPs by gene therapy is emerging as a promising antifibrotic strategy, but the effectiveness of this approach depends on reliable systems for delivering MMP genes. Here, we evaluated a newly designed hyaluronic acid (HA)-shielded delivery system for systemic administration of plasmid DNA encoding MMP13 (pMMP13), and tested whether the enhanced expression of MMP13 ameliorates liver fibrosis in mice. In the CCl(4)-induced liver fibrosis model, systemic administration of pMMP13 using HA and polyethylenimine (PEI) significantly increased the expression of MMP13 and reduced collagen deposition. Moreover, following delivery of pMMP13 in a HA-shielded PEI complex, the serum levels of aspartate transaminase were reduced to levels approaching those in untreated normal mice. These results indicate that the delivery of pMMP13 using HA-shielded PEI enhances the efficiency of MMP13 expression in the liver, and highlight the potential of pMMP13 gene therapy as an antifibrotic strategy.