Abstract

Targeting Hepatocytes with the Lipid Nanoparticular System in Fatty Liver Disease

Jiong-Wei Wang, Assistant Professor, National University of Singapore

Non-alcoholic fatty liver disease (NAFLAD) is a spectrum of chronic liver disease caused by excessive fat accumulation in the liver, with a prevalence of up to 40% in the United States and in Singapore. NAFLAD can develop into a more severe form, non-alcoholic steatohepatitis (NASH), characterized with liver inflammation and fibrosis, and ultimately cirrhosis and liver cancer. Currently, efficacious drugs reversing the various forms of this disease are not yet available. Here in this talk, I will discuss our recent study that employs the lipid nanoparticles (LNP) for targeted inhibition of a clinically relevant sphingolipid metabolic pathway in the hepatocytes with siRNA. With this LNP-siRNA approach, we achieved effective lowering of both hepatic and circulating ceramides and improved therapeutic indexes in animal models of non-alcoholic fatty liver disease. Apart from biochemical and histological evidence, the therapeutic efficacy was also confirmed by our recently developed myeloperoxidase-responsive MRI imaging. This proof-of-concept study demonstrates the feasibility of LNP siRNA system for the treatment of metabolic diseases.