Abstract
Hydrodynamic gene delivery has emerged as an effective method for gene transfer in vivo especially to the liver, and the liver-targeted hydrodynamic procedure has been evaluated in various animal models including rats, pigs, and dogs. In an effort to use hydrodynamic gene delivery for treatment of liver diseases that are commonly fibrotic, we have systematically examined the effect of liver fibrosis on efficiency of hydrodynamic gene delivery. Rat liver fibrosis model was developed by the bile duct ligation (BDL) procedure and hyaluronic acid (HA), a serum marker for liver fibrosis, was used to determine the degree of liver fibrosis. Gene delivery efficiency was assessed using luciferase reporter gene plasmid (pCMV-Luc) in normal rats (n=20) and BDL performed rats (liver fibrosis group, n=20) 10 weeks after the BDL, when liver fibrosis group showed significantly higher serum HA concentration of 231±167 ng/ml than that of 28±17 ng/ml in normal rats (p<0.05). The level of luciferase expression showed 2.5×106RLU/mg of protein in liver fibrosis group which was 100-1,000 folds lower than normal rats. This decrease of gene delivery efficiency suggests that liver fibrosis significantly decreases gene delivery efficiency of hydrodynamic gene delivery. The evidence is supported by the recovery of gene delivery efficiency in liver fibrosis group treated by the liver-targeted hydrodynamic delivery of matrix metalloproteinase-13 gene, which achieved 2.2×108RLU/mg of protein (p<0.05 to liver fibrosis group, N.S. to normal rats). The histological analysis using silver staining also showed significantly higher volume of fibrotic tissue in liver fibrosis group than in normal rats and treated group (p<0.05). These results suggest that the fibrotic tissue significantly decrease the gene delivery efficiency of the liver-targeted HGD procedure and the reduction of fibrotic tissue can recover it.
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