title: Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus.
abstract: Chronic hepatitis B virus (HBV) infection is closely related to the development of severe liver complications, including hepatocellular carcinoma. In previous studies, we reported that in vivo long-term HBV suppression in transgenic mice can be achieved without apparent toxicity by short hairpin RNA sequentially delivered using adeno-associated viral (AAV) vectors of different serotypes. Our goal herein was to address the clinical utility of this delivery system and, in particular, to determine whether RNA interference (RNAi) and its ability to induce long-term HBV suppression will modulate the development of HBV-associated liver pathology. As a model system, we used a unique HBV transgenic mouse model, containing a 1.3 times over length of the HBV genome, on the ICR mouse background. These transgenic mice produce high serum HBV titers comparable with human chronic HBV patients, and, importantly, manifest characteristic HBV-associated pathology, including progressive hepatocellular injury and the development of hepatocellular adenoma. Using this system, we injected animals with AAV vectors expressing either HBV-specific or a control luciferase-specific short hairpin RNA and followed animals for a total of 18 months. We report herein that AAV-mediated RNAi therapy profoundly inhibits HBV replication and gene expression, with a significant reduction in hepatic regeneration, liver enzymes and, importantly, the appearance of liver adenomas. Indeed, the therapeutic effect of RNAi correlated with the reduction in HBV titers. Our data demonstrate that appropriately designed RNAi therapy has the potential to prevent formation of HBV-associated hepatocellular adenoma.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Chen
authors.forename: C-M
authors.initials: CM
authors.lastname: Chang
authors.forename: C-P
authors.initials: CP
authors.lastname: Sun
authors.forename: C-P
authors.initials: CP
authors.lastname: Yu
authors.forename: P-Y
authors.initials: PY
authors.lastname: Wu
authors.forename: K-S
authors.initials: KS
authors.lastname: Jeng
authors.forename: C-P
authors.initials: CP
authors.lastname: Hu
authors.forename: P-J
authors.initials: PJ
authors.lastname: Chen
authors.forename: J-C
authors.initials: JC
authors.lastname: Wu
authors.forename: C-H
authors.initials: CH
authors.lastname: Shih
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
authors.forename: M-H
authors.initials: MH
authors.lastname: Tao
mesh_terms: D018248:Adenoma, Liver Cell / Q000097:blood / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000818:Animals; D015152:Blotting, Northern; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D006514:Hepatitis B Surface Antigens / Q000032:analysis / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000473:pathology / Q000628:therapy / Q000821:virology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy* / Q000821:virology; D008114:Liver Neoplasms, Experimental; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D019562:Viral Load; D014779:Virus Replication
chemical_list: D006514:Hepatitis B Surface Antigens; D034741:RNA, Small Interfering; D012367:RNA, Viral; D008156:Luciferases