title: AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers.
abstract: In liver cirrhosis, abnormal liver architecture impairs efficient transduction of hepatocytes with large viral vectors such as adenoviruses. Here we evaluated the ability of adeno-associated virus (AAV) vectors, small viral vectors, to transduce normal and cirrhotic rat livers. Using AAV serotype-1 (AAV1) encoding luciferase (AAV1Luc) we analyzed luciferase expression with a CCD camera. AAV1Luc was injected through the hepatic artery (intra-arterial (IA)), the portal vein (intra-portal (IP)), directly into the liver (intra-hepatic (IH)) or infused into the biliary tree (intra-biliar). We found that AAV1Luc allows long-term and constant luciferase expression in rat livers. Interestingly, IP administration leads to higher expression levels in healthy than in cirrhotic livers, whereas the opposite occurs when using IA injection. IH administration leads to similar transgene expression in cirrhotic and healthy rats, whereas intra-biliar infusion is the least effective route. After 70% partial hepatectomy, luciferase expression decreased in the regenerating liver, suggesting lack of efficient integration of AAV1 DNA into the host genome. AAV1Luc transduced mainly the liver but also the testes and spleen. Within the liver, transgene expression was found mainly in hepatocytes. Using a liver-specific promoter, transgene expression was detected in hepatocytes but not in other organs. Our results indicate that AAVs are convenient vectors for the treatment of liver cirrhosis.
authors.affiliation: Department of Hepatology and Gene Therapy, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Sobrevals
authors.forename: M
authors.initials: M
authors.lastname: Enguita
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez
authors.forename: J
authors.initials: J
authors.lastname: Gonzalez-Rojas
authors.forename: P
authors.initials: P
authors.lastname: Alzaguren
authors.forename: N
authors.initials: N
authors.lastname: Razquin
authors.forename: J
authors.initials: J
authors.lastname: Prieto
authors.forename: P
authors.initials: P
authors.lastname: Fortes
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006499:Hepatic Artery; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000628:therapy*; D008115:Liver Regeneration / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
chemical_list: D008156:Luciferases