1. ¹Institute of Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Apartado Postal 2-123, 44281 Guadalajara, Jalisco, Mexico
2. ²Hospital General de Mexico, Mexico
3. ³Advantagene, Inc., San Diego, California 92024, USA
4. ⁴OPD Hospital Civil Guadalajara, Guadalajara, Mexico

Correspondence: Juan Armendáriz-Borunda, Institute for Molecular Biology in Medicine and Gene Therapy, Apartado Postal 2-123, 44281 Guadalajara, Jalisco, Mexico. Fax: (52)-33-3617-4159. E-mail: armendbo@cucs.udg.mx

Received 19 February 2003; Accepted 26 September 2003.

Abstract

Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 10¹¹ vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.