FXR Agonists as a Treatment for Diarrhoeal Disease

Description:

Introduction

Diarrhoeal disease is known to cause ~ 2 million deaths per year mostly in developing countries and in children < 5 yrs old. In the Western world common causes of diarrhea include infectious diseases, Inflammatory Bowel Disease(IBD), Irritable Bowel Syndrome (IBs), allergic diarrhoea, celiac disease and liver diseases. In the United states IBD, IBS and IDs alone cost the exchequer ~ $9.6 billion in 2000. Furthermore, diarrhoea is often a debilitating and dose-limiting side effect of cancer chemotherapy. Current treatments such as anti inflammatory drugs and those that alter intestinal motility are indirect and have associated side effects. To date, there are no drugs available that safely and specifically target epithelial transport processes in treatment of diarrhoea.

Technology

The FXR is a relatively newly identified protein that is expressed in the liver and intestine where it acts as a nuclear receptor for bile acids. There has been much interest in therapeutically exploiting the FXR in conditions of liver disease and diabetes. This invention describes a new use for agonists of the FXR in treatment of diarrhoeal disease. RCSI findings show that the FXR is expressed in intestinal epithelial cells and that agonists of the FXR have the capability to alter epithelial transport capacity. Such agonists therefore have the potential to treat disease conditions associated with dysregulated epithelial transport processes. Epithelial cells line the surface of the intestinal tract and are responsible for regulating the movement of fluid to and from the body. Fluid movement is driven by the active transport of ions and the establishment of osmotic gradients and in the intestine, it is the secretion of Cl- ions that is the primary driving force for fluid secretion. To date a potential role for the FXR in regulating epithelial transport processes has not been reported. However RCSI researchers have shown that agonists of the FXR inhibit chloride ion secretion across intestinal epithelial cells.

Applications

Activation of the FXR significantly inhibits the ability of intestinal epithelial cells to evoke agonist-induced Cl- secretory responses both in vitro and in vivo. Since Cl- ion secretion is the primary driving force for fluid secretion in the intestine, in vivo, such effects of FXR activation are expected to inhibit fluid secretion into the intestine.

Dysregulated fluid transport, leading to the onset of diarrhoea, is a feature of many intestinal disorders and these data suggest that drugs that target the FXR may be useful in treating such diseases. This idea is further supported by recently published data showing that, in clinical trials for diabetes, constipation was the main side effect of FXR agonists.

Advantages

Feature	Benefit
Directly targets intestinal epithelial secretion	Avoid unnecessary side effects of indirect treatments eg constipation
Useful in treating a wide range of diarrhoeal diseases of different causes	Large potential market
Commercially available agonists of the FXR exist	Facilitates development