The overall goal of this program is the development and commercialization of a novel, safe, and effectivetherapy for diabetic cardiovascular disease (dCVD). The worldwide prevalence of diabetes has risen from 108million in 1980 to 422 million in 2014 and is expected to increase to 700 million by 2045. Ninety percent ofthose with diabetes have type 2 diabetes (T2D), and 35% of those with T2D have cardiac dysfunction. Thosewith T2D are 2-3 times more likely to develop dCVD. Cardiovascular complications due to hyperglycemia,especially myocardial infarction and heart failure, are the leading cause of T2D-related morbidity and mortality,accounting for 68% of all diabetic deaths. NovoMedix has developed safe, first-in-class, oral drugs that have the potential to prevent dCVD andsignificantly improve long term outcomes for those with T2D by activating AMPK, inhibiting mTOR, preventingactivation of the inflammasome, and inhibiting secretion of IL-11. We, therefore, seek to demonstrate thatNovomedix's leading compound (NMLC) is cardioprotective in diabetic mice and provides protection againstmyocardial infarction following ischemia/reperfusion (I/R) injury. NMLC is an allosteric AMPK agonist, anindependent specific inhibitor of mTORC1 and an inhibitor of IL-11 secretion that prevents heart failure in amouse TAC model and decreases fibrosis and inflammation in liver and lung fibrosis models in mice. NMLCshould reduce/reverse disease progression in dCVD by: 1) improving lipid and glucose homeostasis byactivating AMPK; 2) reducing oxidative stress, inhibiting the production of ROS, and reducing inflammation byinhibition of the NLRP3 inflammasome and activation of AMPK; and 3) providing cardioprotection against I/Rinjury by activating AMPK and independently inhibiting mTOR, and 4) preventing post-I/R cardiac fibrosis byinhibition of IL-11 and mTOR and activation of AMPK. Dr. Das and Dr. Salloum (VCU) recently tested NMLCin diabetic mice and in isolated diabetic mouse adult ventricular cardiomyocytes. NMLC improved metabolicparameters in diabetic mice and protected cardiomyocytes (isolated from diabetic mice) following simulatedischemia/reoxygenation (SI/RO) injury. As a result of the unique potential of this drug to protect the heart against I/R injury in diabetic condition, wepropose the following specific aims: 1) confirm NMLC mechanism of cardioprotection in vitro, assess inhibitionof IL-11 in cardiac fibroblasts, assess AMPK/mTOR signaling in human cardiomyocytes in an SI/RO modelwith high glucose, and scale up NMLC for in vivo studies; 2) examine the cardiometabolic impact of NMLC in amouse model of T2D, determine the effect of NMLC on metabolism and diabetes-induced changes in cardiacfunction, and confirm mechanism of cardioprotection of NMLC in vivo; and 3) determine the beneficial effect ofNMLC in the post-myocardial infarction in db/db mice, determine the effect of NMLC on myocardial infarct andfibrosis after I/R injury, and confirm mechanism of cardioprotection of NMLC in the post-ischemic heart.
Public Health Relevance Statement: Project Narrative
The rising prevalence of diabetes is a grave concern in universal healthcare. Worldwide, more than 380
million people have type 2 diabetes, and 35% of these have cardiac dysfunction. Cardiovascular complications
due to hyperglycemia, especially heart failure, account for 68% of all diabetic deaths. The goal of this program
is to discover and ultimately commercialize a safe, first-in-class, oral therapy for diabetic cardiovascular
disease.
Project Terms: Accounting ; Adult ; 21+ years old ; Adult Human ; adulthood ; Animals ; inhibitor/antagonist ; inhibitor ; Atherosclerosis ; Atheroscleroses ; Atherosclerotic Cardiovascular Disease ; atheromatosis ; atherosclerotic disease ; atherosclerotic vascular disease ; Cardiovascular Diseases ; cardiovascular disorder ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Cause of Death ; Collagen ; Cessation of life ; Death ; Diabetes Mellitus ; diabetes ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Fibroblasts ; Fibrosis ; Future ; Genes ; Glucose ; D-Glucose ; Dextrose ; Goals ; Heart ; Heart failure ; cardiac failure ; Human ; Modern Man ; Hyperglycemia ; hyperglycemic ; Hypertrophy ; In Vitro ; Inflammation ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Insulin Resistance ; insulin resistant ; Ischemia ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lipids ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Myocardial Infarction ; Cardiac infarction ; Myocardial Infarct ; cardiac infarct ; coronary attack ; coronary infarct ; coronary infarction ; heart attack ; heart infarct ; heart infarction ; Myocarditis ; cardiac inflammation ; Patients ; Play ; pressure ; Production ; Pulmonary Fibrosis ; lung fibrosis ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Reperfusion Therapy ; reperfusion ; Reperfusion Injury ; Ischemia-Reperfusion Injury ; Reperfusion Damage ; Role ; social role ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Testing ; Time ; Toxicology ; Transforming Growth Factor beta ; Bone-Derived Transforming Growth Factor ; Milk Growth Factor ; Platelet Transforming Growth Factor ; TGF B ; TGF-beta ; TGF-β ; TGFbeta ; TGFβ ; Transforming Growth Factor-Beta Family Gene ; Up-Regulation ; Upregulation ; Interleukin-11 ; IL-11 ; IL11 ; Healthcare ; health care ; Myocardial Ischemia ; Ischemic Heart ; Ischemic Heart Disease ; Ischemic myocardium ; cardiac ischemia ; coronary ischemia ; heart ischemia ; myocardial ischemia/hypoxia ; myocardium ischemia ; Injury ; injuries ; improved ; Chronic ; Phase ; Myofibroblast ; Cardiac Myocytes ; Cardiac Muscle Cells ; Cardiocyte ; Heart Muscle Cells ; Heart myocyte ; cardiomyocyte ; Serum ; Blood Serum ; disability ; heart function ; cardiac function ; function of the heart ; Stimulus ; Conscious ; Consciousness ; Individual ; Liver Fibrosis ; fibrotic liver ; hepatic fibrosis ; diabetic ; Oxidative Stress ; Disease Progression ; Agonist ; Metabolic ; Myocardial depression ; cardiac dysfunction ; heart dysfunction ; Myocardial dysfunction ; programs ; Severities ; Event ; Oral ; cardiac fibrosis ; myocardial fibrosis ; coronary fibrosis ; interstitial ; hospital re-admission ; re-admission ; re-hospitalization ; readmission ; rehospitalization ; hospital readmission ; Toxicities ; Toxic effect ; novel ; diabetic cardiopathy ; diabetic cardiopathy disease ; diabetic cardiopathy disorder ; diabetic cardiovascular disease ; diabetic cardiovascular disorder ; diabetic cardiomyopathy ; Modeling ; response ; Myocardial Diseases ; Myocardial Disorder ; Myocardiopathies ; myocardium disease ; myocardium disorder ; Cardiomyopathies ; preventing ; prevent ; cardiac hypertrophy ; Heart Hypertrophy ; FK506 Binding Protein 12-Rapamycin Associated Protein 1 ; FKBP12 Rapamycin Complex Associated Protein 1 ; FRAP1 ; FRAP2 ; Mechanistic Target of Rapamycin ; RAFT1 ; mTOR ; mammalian target of rapamycin ; FRAP1 gene ; in vivo ; Pathologic ; Ventricular ; Cardiac ; Development ; developmental ; db/db mouse ; Outcome ; blood glucose regulation ; glucose control ; glucose homeostasis ; glucose regulation ; scale up ; Diabetic mouse ; diabetes mouse model ; Population ; Prevalence ; Impairment ; clinically relevant ; clinical relevance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mitochondrial dysfunction ; mouse model ; murine model ; non-diabetic ; nondiabetic ; commercialization ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; effective therapy ; effective treatment ; diabetic patient ; Inflammasome ; cardioprotection ; cardioprotectant ; cardioprotective ; cardiometabolism ; cardiometabolic ; ischemic injury ; ischemia injury ;
