Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in children and adults associated with diet-associated hepatic lipid accumulation (steatosis), and is a common hepatic manifestation of obesity and metabolic syndromes including diabetes. Modulation Therapeutics is developing a stearoyl- coenzyme A desaturase-1 (SCD1) inhibitor for the treatment of NAFLD and NASH. The novel lead molecule referred to as MTI-301 is orally bioavailable and well-tolerated. Pilot data with MTI-301 in mice fed a Western high fat diet attenuated the liver steatosis and significantly improved liver function. We will leverage data generated in pre-clinical models of both a Western high fat diet as well as a Methionine-choline-deficient (MCD) diet to test the efficacy of MTI-301 as anti-steatosis single agent treatment option. In this proposal we will test our central hypothesis that sustained inhibition of SCD1 with the clinical lead molecule, MTI-301 as a single agent, will attenuate hepatic lipogenesis, reduce triglyceride accumulation, as well as reduce the liver injury, in diet-induced rodent models of NAFLD/NASH. To test our hypothesis in specific aim 1 we will utilize a well-established murine model of NAFDL and NASH and treat with different doses of MTI-301 In specific aim 2, we will evaluate the combination therapy of MTI-301 with pioglitazone, an anti-diabetic drug. Since obesity and metabolic syndromes contribute to the development of liver steatosis, we expect the combination to be reduce the liver dysfunction significantly. Prevention or reversal of liver steatosis is a significant therapeutic goal which can prevent multiple secondary metabolic disorders which increases morbidity and mortality worldwide.
Public Health Relevance Statement: Narrative: The incidence of liver disease from diet is a clinical concern and better treatment options are required to improve patient outcomes. Modulation Therapeutics is developing a potent and specific SCD1 enzyme inhibitor for the treatment of liver disease. Single agent use will allow for prevention of liver failure.
Project Terms: 21+ years old; Adult Human; adulthood; Adult; Affect; inhibitor; Biological Availability; Bioavailability; Physiologic Availability; Blood; Blood Reticuloendothelial System; Cause of Death; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; Chronic Disease; Chronic Illness; chronic disorder; Coenzyme A; CoA; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; comorbidity; co-morbid; co-morbidity; Diabetes Mellitus; diabetes; Diet; diets; Reducing diet; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Epidemic; Monounsaturated Fatty Acids; Nonesterified Fatty Acids; Free Fatty Acids; Fatty Liver; Liver Steatosis; hepatic steatosis; hepatosteatosis; Patient Care; Patient Care Delivery; Goals; Human; Modern Man; In Vitro; Incidence; Inpatients; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipids; Liver; hepatic body system; hepatic organ system; Liver diseases; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; Liver Function Tests; Medicine; Metabolic Diseases; Metabolic Disorder; Thesaurismosis; metabolism disorder; Methionine; Liver Microsomes; Mitochondria; mitochondrial; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Obesity; adiposity; corpulence; Outpatients; Out-patients; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Phosphotransferases; Kinases; Phosphotransferase Gene; Transphosphorylases; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Play; Rattus; Common Rat Strains; Rat; Rats Mammals; Syndrome; Testing; Triglycerides; Triacylglycerol; palmitoleic acid; 9-hexadecenoic acid; Pioglitazone; stearoyl-coenzyme A; stearoyl-CoA; stearyl-CoA; Measures; Hepatic Failure; Liver Failure; Liver Dysfunction; Oleates; PPAR; Peroxisome Proliferator-Activated Receptors; improved; Hepatic; Clinical; Phase; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; liver function; fibrotic liver; hepatic fibrosis; Liver Fibrosis; enzyme activity; Agonist; Toxicokinetics; Therapeutic; Attenuated; attenuate; attenuates; non-alcoholic fatty liver; non-alcohol fatty liver; nonalcohol fatty liver; nonalcoholic fatty liver; Oral; Reaction; Benchmarking; Best Practice Analysis; benchmark; lipid biosynthesis; adipogenesis; lipogenesis; desaturase; attenuation; novel; validation studies; Prevention; Appearance; Modeling; Enzyme Inhibitor Drugs; Enzyme Antagonist; Enzyme Inhibitor; Enzyme Inhibitor Agent; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; gene repression; Gene Down-Regulation; Transcription Repression; Transcriptional Repression; insulin sensitivity; Antidiabetic Drugs; Anti-diabetic Agents; Antidiabetic Agents; anti-diabetic; anti-diabetic drugs; antidiabetic; Metabolic syndrome; fatty acid oxidation; preventing; prevent; Progressive Disease; Dose; DNA Sequence Alteration; DNA Alteration; DNA mutation; Genetic mutation; Sequence Alteration; genomic alteration; Data; Pre-Clinical Model; Preclinical Models; in vivo; Clinical Management; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Rodent Model; Enzyme Inhibition; socioeconomics; socio-economic; socio-economically; socioeconomically; Population; murine model; mouse model; choline deficient diet; NASH; non-alcohol induced steatohepatitis; non-alcoholic steato-hepatitis; non-alcoholic steatohepatitis; nonalcoholic steato-hepatitis; nonalcoholic steatohepatitis; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; new therapeutic target; FDA approved; treatment strategy; bio-markers; biologic marker; biomarker; Biological Markers; efficacy testing; Injury to Liver; hepatic damage; hepatic injury; liver damage; liver injury; western-style diet; western-type diet; western diet; liver development; High Fat Diet; clinical development; NAFLD; non-alcohol fatty liver disease; non-alcoholic liver disease; nonalcoholic fatty liver disease; non-alcoholic fatty liver disease; Metabolic dysfunction; Type II diabetic; Type 2 diabetic; pharmacologic
