Gene therapy of chronic liver injury with RNAi vector targeting TGF-beta receptor

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Transforming growth factor beta (TGF-B) receptor II (TGF-BRII), which is essential for TGF-B signaling and is involved in the causation or participates in the pathway of various human disorders, is consequently considered a key target for therapeutics and analysis of the pathophysiology associated with disruption of the TGF-B system. In the liver, TGF-B plays an essential role in hepatocyte apoptosis, growth inhibition, and progression of fibrogenesis. There is a critical need to introduce technology involving the TGF-B system, such as RNA interference (RNAi), which has high potential for in vivo therapeutics and analytical activities. Here, we investigated the effect of short hairpin RNA targeting TGF-BRII, using hepatocyte injury in human and mouse cell lines and liver injury mouse models. We demonstrated that short hairpin RNA targeting TGF-BRII can be used to silence TGF-BRII genes in mouse and human cell lines, and physiologic and morphologic changes in hepatocytes suffering from acute injury are spared by RNAi-mediated gene silencing of the target gene and by suppressing downstream signal transduction. Furthermore, short hairpin RNA targeting TGF-BRII protected mice from life-threatening acute liver failure.