Treating Alcoholic Liver Fibrosis by Reversal of Type I Collagen

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DESCRIPTION (provided by applicant): Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries. Alcoholic liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) in the liver. Type I collagen is the major component of ECM and it is encoded by the collagen 11(I) gene. Hepatic stellate cells (HSCs) are the main producers responsible for the excessive production of type I collagen in a ~70-fold increase in fibrotic liver compared to the normal liver. The increase of type I collagen in the fibrotic liver is primarily because of the increased half-life of its mRNA from 1.5 hours in quiescent HSCs to greater than 24 hours is activated HSCs. It has been found that the collagen 11(I) mRNA is stabilized by the RNA-binding protein 1CP (encoded by PCBP2 gene) which binds to the 3' end of collagen 11(I) mRNA in activated HSCs, but not in the quiescent HSCs. Therefore, blocking PCBP2 expression is a potential therapeutic approach to decrease the stability of collagen 11(I) mRNA and finally reverse the accumulated type I collagen in the alcoholic fibrotic liver. Potent knockdown of the target gene with high sequence specificity makes siRNA a very promising therapeutic strategy to silence the PCBP2 gene. We have designed and identified one siRNA which can significant silence the PCBP2 gene and consequently decrease the level of 11(I) mRNA. Backbone modification and cholesterol conjugation will be conducted for this siRNA to increase its cellular uptake and achieve the target delivery to the fibrotic liver. Our overall hypothesis is that the reversal of accumulated type I collagen is the critical step in the treatment of alcoholic liver fibrosis. The specific hypotheses are: i) down-regulation of type 1 collagen expression will lead to the recovery of alcoholic liver fibrosis; ii) blocking PCBP2 expression with siRNA will lead to the degradation of stabilized collagen 11(I) mRNA and accordingly induce the reversal of accumulated type I collagen; iii) backbone modification of siRNA will increase its stability without interrupting its activity; iv) conjugation of cholesterol with siRNA will increase its hepatic uptake and consequently achieve the antifibrotic effect. The objective is to develop an effective siRNA therapeutics targeting PCBP2 to decrease the stability of 11(I) mRNA and then induce the reversal of accumulated type I collagen in the alcoholic liver fibrosis. Public health relevance: Alcoholic liver fibrosis is a global health problem, especially in developed countries. Successful accomplishment of this project will provide an effective therapeutics to treat alcoholic liver fibrosis by inducing degradation of the accumulated type I collagen.