Treatment Strategy for Organ Fibrosis Targeting TGF-β and Smad Signaling

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Background & Aims : TGF-β and its intracellular mediators, Smad proteins, play important roles in stimulating collagen gene transcription, and thus could be the targets for treating organ fibrosis. However, intervention of the TGF-β/Smad signal affects physiological signal transduction as well, and may cause serious adverse effects upon clinical application. We have attempted to suppress liver fibrosis by expressing a TGF-β/Smad antagonist selectively in collagen-producing cells only in the fibrotic liver. Methods : Recombinant adenoviruses expressing either GFP or a TGF-β/Smad signal repressor, YB-1, were injected to the mice untreated or treated with carbon tetrachloride (CCl_4). GFP fluorescence was analyzed under a confocal laser-scanning microscopy. Anti-fibrotic effects of YB-1 overexpression were examined by luciferase assays and histological examination using transgenic reporter mice. Results : When using the CAG expression unit as a control, GFP was strongly expressed in a large number of hepatocytes in both normal and CCl_4-treated liver. In contrast, GFP expression driven by a tissue-specific enhancer of the mouse α2(I) collagen gene (COL1A2) was detected in activated hepatic stellate cells in CCl_4-induced fibrotic liver, but not in untreated normal liver. There was no GFP fluorescence observed in any other organs when using the COL1A2 enhancer. Adenovirus-mediated YB-1 expression under the control of the COL1A2 enhancer significantly decreased COL1A2 promoter activity following CCl_4 injection and subsequently suppressed the progression of liver fibrosis. Conclusions : These results validate a new concept of the therapy for hepatic fibrosis to achieve cell type-specific gene expression only in the fibrotic liver with little damage to other organs.