Oligonucleotide inhibition of Fas as a potential treatment strategy in human liver disease.

Abstract

Fas (CD95 or APO-1) is a member of tumor necrosis factor receptor (TNFR) family. Upon activation, by either binding with Fas ligand or self-aggregation, Fas signaling leads to cell apoptosis. Fas is believed to play a role in T-cell- and B-cell-mediated cytotoxicity and depletion; however, Fas is also constitutively expressed in many tissues, including liver. While the function of Fas in normal liver is unclear, many studies have demonstrated that Fas expression in liver is up-regulated under certain inflammatory conditions. A number of clinical reports also indicate that Fas expression and apoptosis are correlated with damage in liver during progression of several hepatic diseases. Therefore Fas may represent an attractive therapeutic target to control excessive or abnormal apoptosis in liver. One approach to regulate Fas expression in vivo is to use antisense oligonucleotides. This class of compound have been shown to be effective inhibitors of gene expression in many organs, including liver, and we have demonstrated protection of liver from apoptotic injury in animals by treatment with antisense oligonucleotides that inhibit Fas. In this article, we describe the evidence of a role for Fas in mediating some forms of liver disease and we review how antisense oligonucleotides can be used to prevent or control this pathology.