Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice.
OBJECTIVE
Adeno-associated virus (AAV) vectors can achieve long-term gene expression and are now feasible for use in human gene therapy. We constructed hepatocyte growth factor (HGF) expressing AAV (AAV5-HGF) and examined its effect in two mouse hepatic fibrosis models.


METHODS
A model of hepatic fibrosis was established by carbon tetrachloride (CCl(4)) administration in Balb/c mice. After the establishment of liver fibrosis, AAV5-HGF was injected once into the portal vein. Mice were killed 3, 6, 9, and 12 weeks after injection. Another model was established by bile duct ligation (BDL). Seven weeks after AAV5-HGF injection, mice underwent BDL, and were then killed 2 weeks after BDL.


RESULTS
Mice that received AAV5-HGF achieved stable HGF expression both in the serum and liver for at least 12 weeks. In both models, significant improvement of the liver fibrosis was found in all mice receiving AAV5-HGF based on Azan-Mallory staining. Suppression of hepatic stellate cells (HSC) was confirmed by immunohistochemistry. Fibrogenic markers were significantly suppressed and collagenase activity increased in the livers of mice receiving AAV5-HGF.


CONCLUSIONS
A single injection of AAV vector containing HGF gene achieved long-term expression of HGF and resulted in resolution of mouse liver fibrosis. HGF gene therapy mediated by AAV is feasible for the treatment of liver fibrosis.
Suzumura
Kazuhiro
K
First Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan.
Hirano
Tadamichi
T
Son
Gakuhei
G
Iimuro
Yuji
Y
Mizukami
Hiroaki
H
Ozawa
Keiya
K
Fujimoto
Jiro
J