Acute pancreatitis therapy by RORα activation and FGF21 expression

Pancreatitis in humPancreatitis in humans is a cause of significant morbidity and mortality.

Acute pancreatitis events have increased worldwide over the last 20-years at an average annual percent change of 3% and the economic burden is growing (1). Treatments for pancreatitis are currently limited. The overall mortality rate in acute severe pancreatitis is 10-15%. Thus, a specific treatment for pancreatitis is of great need.

Recent reports suggest that FGF21 can ameliorate acute pancreatitis in mice.

FGF21 is a protein which belongs to the fibroblast growth factor family and is predominantly produced and secreted by the liver. FGF21 is positively regulated by the ROR transcription factor.

I will assess whether a ROR agonist that we identified by screening compounds that act against Non-Alcoholic Steatohepatitis (NASH) in mice, and which we found to increase FGF21 expression, can be used to treat acute pancreatitis (2).

In addition, we will also investigate whether increased FGF21 expression can be used to prevent pancreatitis triggered by Endoscopic Retrograde CholangioPancreatography (ERCP). We established the Caerulein and alcohol induced pancreatitis models.

In the Caerulein model we show [unpublished and patented (US Pending Patent 11,865,090)] significant therapeutic effects of a small compound that activates ROR.

In this PoC, we intend to explore new compounds of the same family with better efficacy on FGF21 in vivo, and improve the treatment for acute pancreatitis.

This study will establish FGF21 as a prognostic biomarker for acute pancreatitis in humans, by plasma ELISA and circulating free DNA.

This PoC project has the potential to achieve a breakthrough therapeutic treatment for acute pancreatitis; one that is commercially viable, effective, avoids an immune response and has the benefits of a natural delivery, a natural chemical composition of FGF21, lower cost, higher availability, simple storage and overcomes the short half-life of synthetic proteins.