Project Grant R43DK134242

NEW THERAPY FOR THE TREATMENT OF PRIMARY BILIARY CHOLANGITIS. - PROJECT SUMMARY PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC DISEASE IN WHICH THE SMALL BILE DUCTS IN THE LIVER BECOME INJURED AND INFLAMED AND EVENTUALLY DESTROYED. WHEN BILE DUCTS ARE DEPLETED, THE RESULTING BILE BUILD UP RESULTS IN LIVER DAMAGE, LEADING TO SCARRING, CIRRHOSIS, AND EVENTUALLY LIVER FAILURE. AMONG THE COMMON EARLY SYMPTOMS OF PBC IS ITCHY SKIN (PRURITUS), TIREDNESS, ABDOMINAL PAIN, LOW APPETITE, WEIGHT LOSS AND ARTHRITIS. THIS CHRONIC CHOLESTATIC LIVER DISEASE PREDOMINANTLY AFFECTS WOMEN IN THEIR FOURTH AND SIXTH DECADES. CURRENTLY THERAPEUTIC OPTIONS TO TREAT PBC ARE LIMITED AND MUCH OF THE PHARMACOTHERAPY IS RESTRICTED TO MANAGEMENT OF DISEASE SYMPTOMOLOGY. LYSOPHOSPHATIDIC ACID (LPA) ACTS AS A POTENT SIGNALING MOLECULE WITH WIDE-RANGING EFFECTS ON MANY DIFFERENT TARGET TISSUES, AND IS IMPLICATED AS A MITOGEN ACTING MAINLY THROUGH LPAR1 IN THE DEVELOPMENT OF FIBROSIS IN VARIOUS ORGANS. LPAR1 IS ALSO IMPLICATED IN THE DEVELOPMENT OF ARTHRITIS. MANY OF THESE OBSERVED EFFECTS APPEAR TO INVOLVE LPAR1 ACTIVATION AND MODULATION OF INFLAMMATORY RESPONSES THROUGH NUMEROUS SIGNALING MOLECULES INCLUDING TNFA, IFN, IL-17, CTGF AND TGFSS. IFN AND IL-17 ARE SIGNALING MOLECULES IMPLICATED IN THE DEVELOPMENT OF PBC. PRURITUS IS A SERIOUS SYMPTOM ASSOCIATED WITH PBC WHICH HAS BEEN LINKED TO AUTOTAXIN, THE ENZYME RESPONSIBLE FOR PLASMA LPA PRODUCTION. LPA MAY ACT ON NEURONS THROUGH ITS RECEPTORS OF WHICH LPAR1 IS THE PRINCIPAL RECEPTOR EXPRESSED. THUS, LPAR1 MAY REPRESENT A KEY LOCUS IN THE DEVELOPMENT OF BOTH PATHOLOGIC INFLAMMATION AND SERIOUS QUALITY OF LIFE SYMPTOMS. EPIGEN HAS IDENTIFIED SEVERAL CLASSES OF POTENT AND SELECTIVE LPAR1 ANTAGONISTS FROM WHICH AN INITIAL LEAD COMPOUND EPGN696 AND BACKUP EPGN2154 HAVE DEMONSTRATED PRE-CLINICAL EFFICACY IN OTHER DISEASE MODELS. THESE COMPOUNDS DO NOT SHOW CHOLESTATIC RISK IN HUMAN CELLULAR HEPATO-TOXICITY MODELS COMPARED TO A CLINICAL COMPOUND BMS-986020 WHICH HAS BEEN WITHDRAWN. WE PROPOSE TO PROFILE THE TWO LPAR1 ANTAGONISTS FOR UTILITY IN PBC FOR THEIR ABILITY TO MODULATE KEY INFLAMMATORY SIGNALING MOLECULES IFN AND IL-17 AND ITCH RESPONSES IN PRE-CLINICAL MODELS. COMPLETION OF LEAD PROFILING WILL RESULT IN SELECTION OF A SINGLE LEAD THAT WILL BE EVALUATED IN A PRE-CLINICAL MODEL OF PBC, CONDUCTED AT UNIVERSITY OF CALIFORNIA DAVIS. THESE STUDIES WILL DETERMINE THE FEASIBILITY OF DEVELOPING A LPAR1 ANTAGONIST FOR TREATMENT OF PBC.