Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the world’s population. Many patients with this condition will progress to develop more severe forms of liver disease: non-alcoholic steatohepatitis (NASH) and then cirrhosis. Furthermore, these patients are at an increased risk for liver cancer (hepatocellular carcinoma). This disease and its associated medical complications cost the United States healthcare system an estimated $32 billion per year. Little is known about the pathophysiology behind the disease, and there are currently no FDA-approved treatments. We have recently identified a promising target for treatment of this disease. Our findings, consisting of data from a new genetic mouse model and from human gene association studies, indicate a significant role for this protein in hepatic lipid metabolism. In our knockout mouse model, we observed a remarkable resistance to diet-induced lipid accumulation in the liver. Additionally, we have shown that human gene variants are correlated with body mass index (BMI), a known risk factor for NAFLD. Our preliminary data suggest that knockdown of this target will prevent hepatic lipid accumulation and potentially promote regression of NAFLD. This proposal will evaluate the therapeutic potential of this target in a mouse model of NAFLD. We will target hepatic gene expression using an antisense oligonucleotide (ASO) strategy. ASO compounds have been successfully developed and FDA-approved for several targets and disease conditions. In this proposal, Dr. Gordon’s laboratory will design and synthesize a liver-specific ASO against this novel target, validate its efficiency for knockdown of target gene expression, and test the ASO for therapeutic efficacy in mouse models of fatty liver disease.
Based on current data, Dr. Gordon has filed a provisional patent application through the University of Kentucky Office of Technology Commercialization covering the use of ASO compounds directed against his target. Furthermore, to ensure success in the critical stages of ASO design and synthesis, Dr.
Gordon has initiated a collaboration with a large pharmaceutical company that has significant experience with development and marketing of FDA-approved ASO therapies. It is anticipated that within an 18-month timeframe, an effective ASO can be synthesized, functionally validated, and tested for therapeutic efficacy in mouse models.
Successful completion of this proposal would move this concept to a stage ready for significant commercial investment and provide a major advancement toward a much needed therapeutic option for this serious and widely prevalent medical condition.