title: Truncated active human matrix metalloproteinase-8 delivered by a chimeric adenovirus-hepatitis B virus vector ameliorates rat liver cirrhosis.
abstract: BACKGROUND
  Liver cirrhosis is a potentially life-threatening disease caused by progressive displacement of functional hepatocytes by fibrous tissue. The underlying fibrosis is often driven by chronic infection with hepatitis B virus (HBV). Matrix metalloproteinases including MMP-8 are crucial for excess collagen degradation. In a rat model of liver cirrhosis, MMP-8 delivery by an adenovirus (Ad) vector achieved significant amelioration of fibrosis but application of Ad vectors in humans is subject to various issues, including a lack of intrinsic liver specificity.
  
  
  METHODS
  HBV is highly liver-specific and its principal suitability as liver-specific gene transfer vector is established. HBV vectors have a limited insertion capacity and are replication-defective. Conversely, in an HBV infected cell vector replication may be rescued in trans by the resident virus, allowing conditional vector amplification and spreading. Capitalizing on a resident pathogen to help in its elimination and/or in treating its pathogenic consequences would provide a novel strategy. However, resident HBV may also reduce susceptibility to HBV vector superinfection. Thus a size-compatible truncated MMP-8 (tMMP8) gene was cloned into an HBV vector which was then used to generate a chimeric Ad-HBV shuttle vector that is not subject to superinfection exclusion. Rats with thioacetamide-induced liver cirrhosis were injected with the chimera to evaluate therapeutic efficacy.
  
  
  RESULTS
  Our data demonstrate that infectious HBV vector particles can be obtained via trans-complementation by wild-type virus, and that the tMMP8 HBV vector can efficiently be shuttled by an Ad vector into cirrhotic rat livers. There it exerted a comparable beneficial effect on fibrosis and hepatocyte proliferation markers as a conventional full-length MMP-8Ad vector.
  
  
  CONCLUSIONS
  Though the rat cirrhosis model does not allow assessing in vivo HBV vector amplification these results advocate the further development of Ad-HBV vectors for liver-specific gene therapy, including and perhaps particularly for HBV-related disease.
authors.affiliation: The Liver Diseases Diagnosis and Treatment Center of PLA, Bethune International Peace Hospital, Shijiazhuang, People's Republic of China.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Guo
authors.forename: Zihua
authors.initials: Z
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Fubiao
authors.initials: F
authors.lastname: Kang
authors.forename: Haijun
authors.initials: H
authors.lastname: Li
authors.forename: Baosheng
authors.initials: B
authors.lastname: Li
authors.forename: Zhichen
authors.initials: Z
authors.lastname: Cao
authors.forename: Michael
authors.initials: M
authors.lastname: Nassal
authors.forename: Dianxing
authors.initials: D
authors.lastname: Sun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000628:therapy*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism / Q000627:therapeutic use*; D008856:Microscopy, Fluorescence; D051381:Rats; D014162:Transfection
chemical_list: D003094:Collagen; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8