Published online by Cambridge University Press: 27 August 2009
The anatomy of the normal liver is such that hepatocytes are closely accessible to the bloodstream without intervening basement membranes (Gumuncio & Berkowtiz, 1992). Combined with the fact that the liver is a major organ of detoxifcation, and that it takes up foodstuffs, hormones, chemicals, asialoglycoproteins, metal ions, and a wide variety of other molecules, it is no surprise that the liver is a good candidate for the development of antiviral gene therapy against HCV. The goal of antiviral gene therapy is to make cells resistant to viral infection and/or block the virus life cycle at multiple steps. Antiviral gene therapy could supplement immunotherapy and/or the administration of small molecule inhibitors of NS3, NS5B, or other viral targets. However, the lack of a good animal model in which to study HCV pathogenesis (Chs. 13 and 15) and evaluate various forms of antiviral gene therapy represents a major challenge (see related question 21 in Ch. 24).
Despite these limitations, some progress has been made. For example, HCV-specific ribozymes against the 5' UTR and core region have been shown partially to inhibit virus translation in vitro and in cells transfected with a reporter gene cloned downstream from the HCV 5' UTR and core sequences (Sakamoto, Wu & Wu, 1996; Welch et al., 1996). In these experiments, ribozyme-mediated cleavage of the viral RNA was responsible for the decrease in the levels of virus gene expression.
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