No specific therapies exist for nonalcoholic steatohepatitis (NASH), which affects 2-5% of Americans. The long term goal of this project is to develop DB0930-007-a novel, highly specific, orally available small molecule activator of 5'-AMP-activated kinase (AMPK)-as an innovative treatment for NASH. Preliminary data indicate that administration of DB0930-007 to mice fed a high fat diet (HFD) reduces hepatic cholesterol, triglycerides, free fatty acids, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and ?-glutamyl transpeptidase (GGT) to control diet levels-importantly with no liver toxicity. The HFD model is, on its own, insufficient for the complete analysis of NASH. Notably, the ability of our compound to reduce NASH inflammation is unknown. Accordingly, the Specific Aims for this Phase I project are: 1) Exploit an improved NASH model to determine if DB0930-007 can reverse the metabolic and fibrotic pathologies of NASH. A streptozotocin/HFD procedure will be used 2) Determine the anti-inflammatory effects of DB0930-007. Biochemical, immunohistochemical and cell biological assays will be employed along with our NASH model. The expected outcome of these studies will be the identification of a potential first in class treatment for NASH, ready for further development to GLP/Tox stage. NASH affects up to 5% of the US population and will increase in prevalence with the obesity pandemic. It has no specific treatment. AMPK activators represent a novel, innovative approach that could revolutionize NASH treatment. AMPK activators would be marketed to treat NASH with potentially few side effects.
Thesaurus Terms: 5'-Amp-Activated Protein Kinase;Adverse Effects;Affect;Alanine Transaminase;American;Anti-Inflammatory;Anti-Inflammatory Agents;Aspartate Transaminase;Attenuated;Biochemical;Biological Assay;Biological Models;Cells;Characteristics;Cholesterol;Cirrhosis;Data;Development;Diet;Disease;Effective Therapy;Fatty Acid Glycerol Esters;Fatty Liver;Feeding;Fibrosis;Functional Disorder;Future;Gamma-Glutamyl Transferase;Goals;Hepatic;Hepatotoxicity;Improved;In Vivo;Inflammation;Inflammatory;Inflammatory Marker;Innovation;Insulin Resistance;Intervention;Liver;Liver Diseases;Liver Failure;Liver Fibrosis;Malignant Neoplasm Of Liver;Marketing;Medical;Mercury;Metabolic;Modeling;Mus;Non-Alcoholic Fatty Liver;Nonalcoholic Steatohepatitis;Nonesterified Fatty Acids;Novel;Novel Therapeutics;Obesity;Outcome Study;Pandemic Disease;Pathology;Pharmaceutical Preparations;Phase;Population;Positioning Attribute;Pre-Clinical;Prevalence;Prevention;Primary Carcinoma Of The Liver Cells;Procedures;Protein Kinase;Public Health Relevance;Reducing Diet;Risk Factors;Small Molecule;Staging;Steatohepatitis;Streptozocin;Testing;Therapeutic;Toxic Effect;Triglycerides;United States;Work;
