TY - JOUR
T1 - Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis
AU - Vera, M.
AU - Sobrevals, L.
AU - Zaratiegui, M.
AU - Martinez, L.
AU - Palencia, B.
AU - Rodríguez, C. M.
AU - Prieto, J.
AU - Fortes, P.
N1 - Funding Information:
We thank J Novo for providing rat IGF-I cDNA. Technical assistance by N Razquin and E Casales is thankfully acknowledged. M Wodecki help was essential in rat surgery. We also thank members of the lab for advice and Cristian Smedou and Ruben Hernandez for critical reading of the paper. This work was supported by CICYT (PM1999/0091), CICYT (SAF2003-01804), CICYT (SAF 2002-0327), FIS (01/1310 and 01/0843), Instituto Carlos III (C03/02 and PI051098), Education and Health Department of Navarra Government and through the ‘UTE project CIMA’. MV is an FPI fellow.
PY - 2007/2
Y1 - 2007/2
N2 - Liver transplantation is the only treatment for advanced liver cirrhosis. Therapies halting the progression of the disease are urgently needed. Administration of recombinant insulin-like growth factor-I (rIGF-I) induces hepatoprotective effects in experimental cirrhosis. Therefore, we analyzed the efficacy of a recombinant simian virus 40 vector (rSV40) encoding IGF-I (rSVIGF-I) to prevent cirrhosis progression. First, transgene expression was evaluated in mice injected with rSV40 encoding luciferase, which showed long-term hepatic expression of the transgene. Interestingly, luciferase expression increased significantly in CCl4-damaged livers and upon IGF-I administration, thus liver injury and IGF-I expression from rSVIGF-I should favor transgene expression. rSVIGF-I therapeutic efficacy was studied in rats where liver cirrhosis was induced by CCl4 inhalation during 36 weeks. At the end of the study, the hepatic levels of IGF-I and IGF-binding protein 3 were higher in rSVIGF-I-treated rats than in control cirrhotic animals. Cirrhotic rats treated with rSVIGF-I had reduced serum bilirubin, transaminases and liver fibrosis scores and increased hepatic expression of hepatocyte growth factor and STAT3α as compared to cirrhotic animals. Furthermore, cirrhotic animals showed testis atrophy and altered spermatogenesis, whereas testicular size and histology were normal in cirrhotic rats that received rSVIGF-I. Therefore, rSV40-mediated sustained expression of IGF-I in the liver slowed cirrhosis progression.
AB - Liver transplantation is the only treatment for advanced liver cirrhosis. Therapies halting the progression of the disease are urgently needed. Administration of recombinant insulin-like growth factor-I (rIGF-I) induces hepatoprotective effects in experimental cirrhosis. Therefore, we analyzed the efficacy of a recombinant simian virus 40 vector (rSV40) encoding IGF-I (rSVIGF-I) to prevent cirrhosis progression. First, transgene expression was evaluated in mice injected with rSV40 encoding luciferase, which showed long-term hepatic expression of the transgene. Interestingly, luciferase expression increased significantly in CCl4-damaged livers and upon IGF-I administration, thus liver injury and IGF-I expression from rSVIGF-I should favor transgene expression. rSVIGF-I therapeutic efficacy was studied in rats where liver cirrhosis was induced by CCl4 inhalation during 36 weeks. At the end of the study, the hepatic levels of IGF-I and IGF-binding protein 3 were higher in rSVIGF-I-treated rats than in control cirrhotic animals. Cirrhotic rats treated with rSVIGF-I had reduced serum bilirubin, transaminases and liver fibrosis scores and increased hepatic expression of hepatocyte growth factor and STAT3α as compared to cirrhotic animals. Furthermore, cirrhotic animals showed testis atrophy and altered spermatogenesis, whereas testicular size and histology were normal in cirrhotic rats that received rSVIGF-I. Therefore, rSV40-mediated sustained expression of IGF-I in the liver slowed cirrhosis progression.
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U2 - 10.1038/sj.gt.3302858
DO - 10.1038/sj.gt.3302858
M3 - Article
C2 - 17024107
AN - SCOPUS:33846556910
SN - 0969-7128
VL - 14
SP - 203
EP - 210
JO - Gene Therapy
JF - Gene Therapy
IS - 3
ER -