Introduction: Exposure to toxins from the portal circulation, viral infection and by-products of metabolic activity make liver tissue prone to injury. When sustained, associated inflammation leads to activation of hepatic stellate cells (HSCs), deposition of extracellular matrix (ECM) proteins and complicating hepatic fibrosis.
Areas covered: In this article, the authors discuss utility of therapeutic gene silencing to disable key steps of hepatic fibrogenesis. Strategies aimed at inhibiting HSC activation and silencing primary causes of fibrogenesis, such as viruses that cause chronic hepatitis, are reviewed. Both synthetic and expressed artificial intermediates of the RNAi pathway have potential to treat hepatic fibrosis, and each type of gene silencer has advantages for clinical translation. Silencing expression cassettes comprising DNA templates are compatible with efficient hepatotropic viral vectors, which may effect sustained gene silencing. By contrast, synthetic short interfering RNAs are amenable to chemical modification, incorporation into non-viral formulations, more precise dose control and large scale preparation.
Expert opinion: Clinical translation of RNAi-based technology for treatment of hepatic fibrosis is now a realistic goal. However, achieving this aim will require safe, efficient delivery of artificial RNAi intermediates to target cells, economic large scale production of candidate drugs and specificity of action.
Keywords: Hepatic fibrosis; RNAi; extracellular matrix; hepatic stellate cells; hepatocytes.