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: Jinxia Liu, Xin Cheng, Zhengrong Guo, Zihua Wang, Dong Li, Fubiao Kang, Haijun Li, Baosheng Li, Zhichen Cao, Michael Nassal, Dianxing Sun
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53392 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23301066 (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