Hepatic cirrhosis is the ninth most common cause of death in Japan (“Summary of Monthly Report of Vital Statistics: 2009,” Ministry of Health, Labour and Welfare), and there are approximately 300,000 patients and approximately 3,500,000 potential hepatitis patients in Japan. This disease is an intractable disease in which hardening of the liver tissue occurs due to abnormal accumulation of extracellular matrix proteins. This disease includes a series of pathological conditions where the hardening of the liver (fibrosis of the liver) occurs during repetitions of hepatic impairment and regeneration, and apoptosis of the liver cells consequently occurs, leading to liver failure.
A known major causative factor of the liver fibrosis is activation of the fibrogenic cytokine TGF-β (NPL 1). In hepatic cirrhosis, hepatic stellate cells present between the hepatic sinusoid and hepatic parenchymal cells are activated and start to excessively produce extracellular matrices including collagen. The excessive collagen production and the like are promoted by TGF-β. It has been shown in an animal model that hepatic cirrhosis can be prevented when the action of TGF-β is blocked by a gene therapy or the like (NPL 2). Moreover, hepatic cancer develops from cirrhotic liver at an incidence of 5 to 7 percent per year, leading to death. It is said that TGF-β also plays an important role as a causative factor of the hepatic cancer through induction of EMT (epithelial-mesenchymal transition) and reduction in immunity to cancer due to induction of regulatory T cells (NPL 3).
On the other hand, 76% of the hepatic cirrhosis cases in Japan are caused by hepatitis C virus (HCV) infection. In Japan alone, two million people are estimated to be infected with HCV, and it is said that 200 million people are infected with HCV in the world. Hepatic cirrhosis develops 10 years to 30 years after infection with HCV, and further progresses to hepatic cancer. Hence, this becomes a great social problem. Under such circumstances, a combination therapy of PEGylated interferon with ribavirin is applied at present, and a virus removal effect is observed in 40 to 50% of patients. Moreover, protease activity inhibitors against serine protease NS3 necessary for maturation of virus particles have been developed, and are currently in Phase II to III clinical trials (NPLs 4 to 5).
However, as the mechanism by which HCV causes liver fibrosis and/or hepatic cancer has not been elucidated, no drug has yet been developed which enables a radical treatment for such viral diseases.