759. Liver Transduction with an SV40 Vector Encoding Insulin-Like Growth Factor I Reduces Hepatic Damage and Delays Cirrhosis Progression

Abstract

Top of pageAbstract Circulating insulin-like growth factor I (IGF-I) is mainly of hepatic origin and its levels are markedly decreased in liver cirrhosis. Treatment with IGF-I displays hepatoprotective properties and improves nutrition and hypogonadism in experimental cirrhosis. In this study we analyzed the efficacy of a Simian Virus 40 (SV40)-based vector encoding IGF-I to treat rats subjected to CCl4 inhalation. Recombinant SV40 vectors (rSV40) efficiently infect hepatocytes where they drive durable transgene expression. In this study we found that luciferase expression in rSV40-infected mouse livers can be detected with a CCD camera for more than seven months. Even if expression from rSV40 is low, hepatic luciferase activity significantly increased after induction of liver damage with CCl4. Luciferase levels also increased in response to IGF-I administration, thus favouring transgene expression from IGF-I expressing rSV40 vectors. A rSV40 vector encoding functional IGF-I (rSVIGF-I) was used to infect healthy male Wistar rats in which liver cirrhosis was induced by CCl4 inhalation during 36 weeks. At the end of this period rSVIGF-I-treated rats had normal levels of serum bilirubin and serum transaminases and showed a significant increase of IGFBP3, an IGF-I binding protein positively regulated by IGF-I. Interestingly, fibrosis score was reduced in rats that received CCl4 and rSVIGF-I as compared with control animals given CCl4. Moreover, testis weight was reduced in control cirrhotic rats but was normal in CCl4-treated rats that received rSVIGF-I. These results indicate that the rSVIGF-I vector is an efficient alternative for prevention and treatment of liver cirrhosis development.