An Open-Label Study of Ursolkc Acid for Primary Sclerosing Cholangitis

Project: Research project

Project Details


Primary sclerosing cholangitis (PSC) is a rare liver disease of the bile ducts often associated with inflammatory
bowel disease (IBD) with a median onset of illness of 35 years and mean progression to death or liver
transplantation of 15 years. Currently PSC accounts for approximately 4% of all liver transplants performed in
the US and no medical therapies have been shown to be effective in altering the natural history of the disease.
Our long term goal is to develop safe and effective therapies for the treatment of PSC. Based upon genome
wide association studies and immunologic characterization of the disease, several mechanisms are likely
involved in the pathogenesis of PSC. Two potential targets for PSC include Th17 cells and the G protein-
coupled receptor for bile acids, TGR5. Similar to other inflammatory diseases, Th17 cells are hyper-responsive
in PSC. Variants in the TGR5 gene, a G protein-couple bile acid receptor, have been associated with PSC risk
and appear to correlate with low levels of gene expression. Thus, to potential targets for PSC therapies are
inhibition of Th17 and activation of TGR5. Recently, ursolic acid (UA), a natural triterpenoid, was found to
inhibit Th17 differentiation and IL-17 secretion through its selective antagonist activity on the retinoic acid
receptor-related orphan receptor ROR¿t. In addition, UA has been demonstrated to act as a potent agonist of
TGR5. UA is found in many medicinal plants and has been extensively studied in animal models. The goals of
this study are to 1) measure the pharmacokinetics of orally administered 99%-pure GMP-grade UA in healthy
controls and PSC patients, 2) determine the safety and potential efficacy of UA in the treatment of PSC, and 3)
understand the impact of UA on Th17 function, macrophage activation, and serum bile acid pools in vivo. To
accomplish these goals, we propose a dose escalation study of UA pharmacokinetics, an open label study of
UA in PSC, and correlative studies of UA effects on biologic outcomes.
Effective start/end date3/24/141/31/16


  • National Institutes of Health: $179,043.00
  • National Institutes of Health: $231,120.00


  • Medicine(all)


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