Fibroblast growth factors to combat fatty liver disease

Targeting the fibroblast growth factor system in the treatment of non-alcoholic fatty liver disease (NAFLD)

The liver plays a central role in lipid metabolism. If hepatic lipid metabolism is disturbed, fat can start to accumulate in the liver, leading to a condition called non-alcoholic fatty liver disease (NAFLD). In NAFLD, sustained fat accumulation in the liver can lead to liver damage and a decrease in normal liver function. In this partnership, the UMCG and Merck/MSD will team-up to understand how a new class of drugs called FGFs can improve liver function in NAFLD.

NAFLD is the most common chronic liver disorder worldwide which affects around a quarter of the world population. The development of NAFLD is closely linked to obesity and insulin resistance, and the prevalence of NAFLD among type 2 diabetic (T2D) patients is around 70%. In some patients with NAFLD, fat accumulation in the liver is associated with signs of inflammation or scarring, also called hepatic fibrosis. Hepatic fibrosis is associated with an increased risk of developing end-stage liver disease, hepatocellular carcinomas, and the need for liver transplantation. Unfortunately, there are currently no drugs approved for the treatment of NAFLD.

Several members of the fibroblast growth factor (FGF) family have recently emerged as promising new biologicals in the treatment of NAFLD. In addition, these FGFs may also be useful in the treatment of other serious liver diseases, including primary biliary cholangitis and primary sclerosing cholangitis. Preclinical studies have shown that FGFs exert their therapeutic effects by targeting a protein called beta klotho (KLB). However, there are still many unanswered questions about how this protein works and how it is regulated. It is hypothesizes that loss of KLB function can limit the efficacy of FGF-mimetics. Therefore, understanding the regulation of KLB can provide new strategies to improve the efficacy of FGF-mimetics in the treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide, present in about a quarter of the world population, and is strongly linked to obesity. While early stage NAFLD is benign, it can progress into more serious liver damage such as fibrosis and cirrhosis, ultimately resulting in end-stage liver disease, liver cancer, and the need for liver transplantation. Because there are no approved drugs available to treat NAFLD, there is an urgent need to identify new therapeutic targets that can improve liver health. Fibroblast growth factors (FGF) have recently emerged as promising new biologicals in the treatment of NAFLD and currently several FGF-mimetics are under investigation in different phases of clinical trials. We expect that a better understanding of the mechanism of action of the metabolic FGFs and the regulation of their receptors will increase the safety and efficacy of current and future FGF-based drugs.
Technology Readiness Level (TRL)
1 - 3
Time period
48 months