AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

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...

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Bibliographic Details
Published in:	Gene therapy Vol. 19; no. 4; pp. 411 - 417
Main Authors:	Sobrevals, L, Enguita, M, Rodriguez, C, Gonzalez-Rojas, J, Alzaguren, P, Razquin, N, Prieto, J, Fortes, P
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2012 Nature Publishing Group
Subjects:	Adeno-associated virus Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Applied cell therapy and gene therapy Biological and medical sciences Biomedical and Life Sciences Biomedicine Biotechnology Cameras Care and treatment Cell Biology Cirrhosis Dependovirus - genetics Dependoviruses DNA Expression vectors Fundamental and applied biological sciences. Psychology Gene Expression Gene Therapy Genetic aspects Genetic Therapy - methods Genetic Vectors Genomes Health aspects Health. Pharmaceutical industry Hepatectomy Hepatic Artery Hepatocytes Hepatocytes - metabolism Human Genetics Industrial applications and implications. Economical aspects Integration Liver Liver - metabolism Liver cells Liver cirrhosis Liver Cirrhosis - genetics Liver Cirrhosis - therapy Liver Regeneration - genetics Luciferases - genetics Luciferases - metabolism Male Medical sciences Nanotechnology original-article Physiological aspects Portal Vein Promoters Rats Rats, Sprague-Dawley Rodents Spleen Testes Transducers Transduction, Genetic Transfusions. Complications. Transfusion reactions. Cell and gene therapy Transgenes Vector space Vectors (Biology) Spain recombinant AAV vector luciferase expression TAA CCl liver cirrhosis Rat Liver Hepatic disease Hepatocyte Vector Digestive system Enzyme Luciferase Rodentia Dependovirus Virus Associated virus Cirrhosis In vivo Vertebrata Mammalia Parvoviridae Digestive diseases Transduction Oxidoreductases Gene therapy Parvovirinae
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0969-7128 1476-5462
DOI:	10.1038/gt.2011.119