HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Truncated active human matrix metalloproteinase-8 delivered by a chimeric adenovirus-hepatitis B virus vector ameliorates rat liver cirrhosis.

AbstractBACKGROUND:
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.
AuthorsJinxia Liu, Xin Cheng, Zhengrong Guo, Zihua Wang, Dong Li, Fubiao Kang, Haijun Li, Baosheng Li, Zhichen Cao, Michael Nassal, Dianxing Sun
JournalPloS one (PLoS One) Vol. 8 Issue 1 Pg. e53392 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23301066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Collagen
  • MMP8 protein, human
  • Matrix Metalloproteinase 8
Topics
  • Adenoviridae (genetics)
  • Animals
  • Cell Proliferation
  • Collagen (metabolism)
  • Disease Models, Animal
  • Fibrosis
  • Genetic Therapy (methods)
  • Genetic Vectors (genetics)
  • Hep G2 Cells
  • Hepatitis B virus (genetics)
  • Hepatocytes (cytology)
  • Humans
  • Liver (metabolism)
  • Liver Cirrhosis (metabolism, therapy)
  • Matrix Metalloproteinase 8 (metabolism, therapeutic use)
  • Microscopy, Fluorescence
  • Rats
  • Transfection

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: