Primary biliary cholangitis (PBC) is a serious, chronic cholestatic liver disease characterized by aprogressive, autoimmune-based destruction of the bile duct, and the eventual onset of cirrhosis and itscomplications. There are limited FDA-approved drugs for the management of PBC, but in many casesliver transplantation is required and offers the only chance for a complete cure. Therefore, effectivetreatments are urgently needed to treat PBC and to delay time to liver transplantation and to improvethe quality of life for PBC patients. With that goal in mind, a novel approach for treating PBC isdescribed below. These developments are based on the observation that remogliflozin etabonate, anSGLT2 inhibitor with unique differentiating properties from other SGLT2 inhibitors, prevents theprogression of PBC disease pathology in a murine model of liver damage. Based on our compellingpreliminary data, this Phase I confirmation of proof-of-concept study will demonstrate thatremogliflozin etabonate is a potential therapy for PBC. We will achieve these goals by the followingAims: 1) Evaluate the role of remogliflozin and other SGLT inhibitors in liver cells in vitro. SGLTsare expressed in biliary ducts and inhibition of SGLTs causes increased biliary flow; and 2) Confirm invivo our earlier observation that remogliflozin etabonate can prevent or reverse PBC progression usinga well-accepted murine model of PBC.
Public Health Relevance Statement: Project Narrative
Primary biliary cholangitis (PBC) is a slowly developing disease of the liver. Treatment of
PBC involves liver transplantation with few therapies available. We plan to examine the effects
of the well characterized drug remogliflozin etabonate as a potential treatment for PBC to
address this urgent clinical need.
Project Terms: Hepatic Parenchymal Cell ; Liver Cells ; Serum ; Blood Serum ; residence ; residential building ; residential site ; Oxidative Stress ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Oral Examination ; programs ; Biliary ; stellate cell ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; glucose uptake ; Duct ; Duct (organ) structure ; Sampling ; Property ; Skin ; Onions ; Allium cepa ; preventing ; prevent ; Address ; Data ; in vivo ; Characteristics ; Development ; developmental ; Cirrhosis ; cirrhotic ; Pathway interactions ; pathway ; cholangiocyte ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Outcome ; Mind ; mouse model ; murine model ; FDA approved ; effective therapy ; effective treatment ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; liver injury ; Injury to Liver ; hepatic damage ; hepatic injury ; liver damage ; cholestatic liver disease ; cholestatic liver disorder ; side effect ; clinical examination ; clinical exam ; Autoimmune ; absorption ; Animals ; inhibitor/antagonist ; inhibitor ; Antioxidants ; anti-oxidant ; Bicarbonates ; HCO3 ; Hydrogen Carbonates ; Bile fluid ; Bile ; Bile Juice ; Bile Acids ; bile duct ; bile ductule ; Biochemistry ; Biological Chemistry ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cell physiology ; Cell Function ; Cell Process ; Cellular Function ; Cellular Physiology ; Cellular Process ; Subcellular Process ; Cholangitis ; Primary biliary cirrhosis ; Chronic Non-Suppurative Destructive Cholangitis ; Chronic Nonsuppurative Destructive Cholangitis ; Primary biliary cholangitis ; Clinical Research ; Clinical Study ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Female ; Fibrosis ; Gene Expression ; Glucose ; D-Glucose ; Dextrose ; Glucose Transporter ; Glucose Binding Protein ; Glucose Transport Protein ; Goals ; Histology ; Human ; Modern Man ; In Vitro ; Inflammation ; Interferon Type II ; Gamma interferon ; IFN-Gamma ; IFN-g ; IFN-γ ; IFNG ; IFNγ ; Immune Interferon ; Interferon Gamma ; Interferon-gamma ; lFN-Gamma ; Kupffer Cells ; Stellate Sinusoidal Macrophage ; liver macrophage ; Liver ; hepatic body system ; hepatic organ system ; Liver diseases ; Hepatic Disorder ; hepatic disease ; hepatopathy ; liver disorder ; liver transplantation ; Hepatic Transplantation ; Liver Grafting ; Liver Transplant ; Marketing ; Mus ; Mice ; Mice Mammals ; Murine ; Pathology ; Patients ; Placebos ; Sham Treatment ; sham therapy ; Play ; Prodrugs ; Drug Precursors ; Pro-Drugs ; Proteins ; Quality of life ; QOL ; Research ; Messenger RNA ; mRNA ; Role ; social role ; Sodium ; Na element ; Testing ; Time ; Ursodeoxycholic Acid ; Deoxyursocholic Acid ; Ursacholic Acid ; Ursodiol ; Mediating ; Reactive Oxygen Species ; Active Oxygen ; Oxygen Radicals ; Pro-Oxidants ; base ; improved ; Chronic ; Clinical ; Phase ; Hepatocyte ; Hepatic Cells ;
