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Gene therapy holds promise for treating liver diseases. A review in Gut by Schmitz et al describes significant progress in search of new options based on genetic techniques for treating intractable diseases such as chronic hepatitis B and C infection and primary and secondary liver cancers.
For example, in viral hepatitis gene transfer of IFN α by adenovirus vector prevents the disease in mice, and combined administration of one adenovirus vector containing selected sequences of hepatitis C virus and another containing interleukin 12 genes potentiated a cellular immune response.
In liver cancer drug sensitisation and genetic immunotherapy look promising. Drug sensitisation—transferring a gene for a foreign enzyme to convert a non-toxic prodrug into a anticancer drug—a suicide gene—is best exemplified by the HSV tk gene. The encoded enzyme converts the prodrug gancyclovir into a toxic compound which halts DNA synthesis. Added to this is an appreciable bystander effect—when the metabolite diffuses into the surrounding cells, stimulating local inflammation and antitumour immunity, owing to the death of cancer cells. Unwanted effects on healthy tissue are reduced by injecting the vector locally or limiting gene expression with tumour specific promoters.
Genetic immunotherapy offers ways of stimulating the immune system against cancer cells. Injecting a virus vector encoding interleukin 12 into rats with hepatocellular carcinoma in the liver and into mice with metastatic colon cancer achieved complete eradication of tumours and induced antitumour immunity. Introducing this vector through the intrahepatic artery increased antitumour activity in an aggressive hepatocellular carcinoma model induced by a carcinogen.
Therapeutic approaches with HSV tk and interleukin 12 are sufficiently promising for trials in humans to be under way.