This SBIR proposes development of a new drug for treatment of heart failure, a disease currently responsible for the deaths of ~80,000 people annually in the US. The underlying causes of this condition include myocardial infarction, hypertension and disease of the heart valves. Existing treatments primarily act on the neurohormonal axis to reduce volume overload but despite the availability of these drugs, 5-year mortality following a heart failure diagnosis is approximately 50% and is similar to many cancers. We propose to develop a drug that directly targets cardiac metabolism, reversing the reduced use off at oxidation that occurs in the failing heart and thereby enabling it to maintain its pump function. This will be achieved by drugs that activate estrogen-related receptors (ERRs), a type of nuclear receptor that regulates mitochondrial energy metabolism. There are 3 isoforms of estrogen-related receptors - a, b and g. We have generated data to show that ERR agonists that activate all 3 isoforms protect against the decline in heart function that occurs in the transaortic constriction (TAC) model in the mouse. In this Phase I application we propose to identify agonists that selectively activate individual isoforms (or combinations thereof) and test their effects in the TAC model in order to delineate the isoforms mediating benefit in heart failure. We have selected a short-list of potentially useful tools from the ~560 proprietary compounds that have already been made and will profile them in vitro and in vivo to identify those suitable to be tested in the TAC model. In the course of this work, we will also validate isoform-specific genetic biomarkers for their ability to confirm the activation of the specific isoforms after in vivo dosing of compounds. In Phase II we will use the knowledge gained in Phase I to develop more potent and drug-like ERR agonists, nominate a clinical development candidate and characterize its properties more fully, including in heart failure models other than the TAC model. If successful we hope to improve the survival and quality of life of heart failure patients and save a significant proportion of the 1-2% of health care expenditure that is currently spent treating this condition.
Public Health Relevance Statement: PROJECT NARRATIVE. Heart failure is responsible for the death of ~80,000 people every year in the US. Current therapies are inadequate, as reflected by the ~50% of people who die within 5 years of a heart failure diagnosis. In this Phase I SBIR, Cadre Bioscience seeks to develop a first-in-class agent that will target estrogen-related receptors to reverse the detrimental metabolic changes that occur in heart failure, preventing the decline in pump function that leads to morbidity and death.
Project Terms: Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Capital Financing ; Capital Funding ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Citric Acid Cycle ; Krebs Cycle ; TCA cycle ; Tricarboxylic Acid Cycle ; Cessation of life ; Death ; Diagnosis ; Disease ; Disorder ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Energy Metabolism ; Energy Expenditure ; Health Expenditures ; health care expenditure ; healthcare expenditure ; Fatty acid glycerol esters ; Fats ; Genes ; Genetic Markers ; genetic biomarker ; Glycolysis ; Goals ; Health ; Heart ; Heart failure ; cardiac failure ; Heart Rate ; Cardiac Chronotropism ; Heart Valve Diseases ; Valvular Heart Diseases ; Valvular Heart Disorder ; cardiac valve disease ; cardiac valve disorder ; cardiac valvular disease ; degenerative valvular heart disease ; heart valve disorder ; Hospitalization ; Hospital Admission ; Hypertension ; Vascular Hypertensive Disease ; Vascular Hypertensive Disorder ; high blood pressure ; hyperpiesia ; hyperpiesis ; hypertensive disease ; In Vitro ; Life Expectancy ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Mitochondria ; mitochondrial ; 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 ; Myocardium ; cardiac muscle ; heart muscle ; oxidation ; Oxidative Phosphorylation ; Oxidative Phosphorylation Pathway ; Patients ; Pharmacology ; Quality of life ; QOL ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Rights ; Technology ; Testing ; Work ; Mediating ; base ; Pump ; improved ; Phase ; Series ; Reporter Genes ; Nuclear Receptors ; heart function ; cardiac function ; function of the heart ; Individual ; Licensing ; Skeletal Muscle ; Voluntary Muscle ; Agonist ; Developed Countries ; Industrialized Countries ; Industrialized Nations ; developed country ; developed nation ; developed nations ; Therapeutic ; Metabolic ; tool ; Knowledge ; Ejection Fraction ; EFRAC ; Inferior ; cardiac metabolism ; heart metabolism ; Myocytes ; Muscle Cells ; Isoforms ; Protein Isoforms ; Receptor Protein ; receptor ; Structure ; novel ; technological innovation ; Modeling ; Property ; fatty acid oxidation ; preventing ; prevent ; Dose ; Academia ; Data ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Myocardial ; Ventricular ; Development ; developmental ; knock-down ; knockdown ; Outcome ; Neonatal ; Population ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; commercial application ; standard of care ; constriction ; estrogen-related receptor ; mitochondrial metabolism ; novel drug class ; new drug class ; clinical development ; societal costs ; preservation ; effectiveness testing ;
