Alcoholic Cardiomyopathy (ACM) is the most prevalent form of ethanol-induced heart damage. Alcohol dose-dependently induces ACM, characterized by progressive reduction in myocardial contractility and ventricular dilatation, culminating in heart failure. At the cellular level, chronic alcohol consumption results in cardiomyocyte death, cardiac inflammation, and cardiac fibrosis. There are currently no FDA-approved therapies for ACM. The long-term goal of this project is to advance emodin, a small molecule natural compound with anti-inflammatory, anti-apoptotic, and anti-fibrotic activities, for ACM prevention or treatment. We have generated a robust body of background data in the basic science and early discovery phase that supports emodin as a novel therapy for ACM including: 1) TGFß signaling is the primary underlying mechanism responsible for alcohol-induced cardiac fibrosis, a key component of ACM pathogenesis, 2) Emodin is an effective inhibitor of TGFß canonical and non-canonical signaling in multiple cell types, 3) The pharmacokinetics (PK) and excellent safety of emodin have been examined in murine models, and 4) At non- toxic oral doses, emodin effectively ameliorates cardiac fibrosis and dysfunction associated with doxorubicin, a pathology similar to ACM. Furthermore, our preliminary data illustrates that emodin attenuates alcohol-induced loss of cardiomyocyte viability and activation of cardiac fibroblasts. We propose to further test the central hypothesis that emodin can be developed as a safe and effective preventive and/or therapeutic agent for ACM. In this Phase 1 STTR application, we propose to examine the PK, safety, and efficacy of emodin in chronic alcohol consumption rodent models and perform a PK and toxicity study in pigs in the following three specific aims. SA1. To test if alcohol consumption influences emodin metabolism and evaluate the safety and efficacy of emodin in ameliorating ACM in mouse models. SA2. To examine the PK, safety, and efficacy of emodin in reducing cardiac fibrosis and cardiac dysfunction in alcohol-fed rats in both prevention and treatment settings. SA3.To perform a PK and safety study of emodin in pigs and find a safe dose range that may achieve effective blood emodin concentrations. By the end of the funding period of this STTR Phase 1 application, we will possibly move emodin towards the next phase of drug development: IND-enabling preclinical study. Milestones for a Go/no-go decision include: 1) if emodin does not exaggerate alcohol-induced toxicities in mice and rats, particularly liver toxicity; 2) if there is significant efficacy of emodin in ameliorating ACM in mice and rats; and 3) if an appropriate safe dose is identified in pigs that can be extrapolated to humans. If answers to the above three questions are positive, the decision will be made to further the development process of emodin, and a Phase II application will be submitted to perform an IND-enabling preclinical study, including 1) safety and efficacy studies in pig ACM models in a GLP setting, and 2) formulation and cGMP manufacturing of emodin capsule for human use.
Public Health Relevance Statement: Project narrative: Alcoholic Cardiomyopathy (ACM) is the most prevalent form of ethanol-induced heart damage. There are currently no FDA-approved therapies for ACM. We propose to develop a pleiotropic natural compound emodin as a therapy for the prevention and treatment of ACM.
Project Terms: Alcohol Drinking; EtOH drinking; EtOH use; alcohol ingestion; alcohol intake; alcohol product use; alcohol use; alcoholic beverage consumption; alcoholic drink intake; ethanol consumption; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; Alcohol consumption; Absolute ethanol; ETOH; Ethyl Alcohol; Grain Alcohol; Methylcarbinol; Ethanol; Alcohol Chemical Class; Alcohols; Anatomic Sites; Anatomic structures; Anatomy; inhibitor; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Arrhythmia; Cardiac Arrhythmia; Heart Arrhythmias; Blood; Blood Reticuloendothelial System; Body Weight; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; capsule; Capsules; Alcoholic Cardiomyopathy; alcohol-induced heart muscle disease; alcoholic heart muscle disease; Data Reporting; data representation; data representations; Cessation of life; Death; Dilatation - action; Dilatation; Disease; Disorder; Doxorubicin; 14-Hydroxydaunomycin; Adriamycine; Doxorubicina; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Emodin; 1, 3, 8-trihydroxy-6-methyl-9, 10-anthracenedione; 3-Methyl-1, 6, 8-trihydroxy-antraquinone; Archin; Frangula Emodin; Frangulic Acid; Rheum Emodin; Fibroblasts; Future; Goals; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Heart; Heart failure; cardiac failure; Human; Modern Man; Literature; Liver; hepatic body system; hepatic organ system; Metabolism; Intermediary Metabolism; Metabolic Processes; Inbred BALB C Mice; BALB C Mouse; BALB/c; Mus; Mice; Mice Mammals; Murine; Myocarditis; cardiac inflammation; Necrosis; Necrotic; Pathology; Drug Kinetics; Pharmacokinetics; Wistar Rats; Rattus; Common Rat Strains; Rat; Rats Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Family suidae; Pigs; Suidae; Swine; porcine; suid; Testing; Transforming Growth Factor beta; Bone-Derived Transforming Growth Factor; Milk Growth Factor; Platelet Transforming Growth Factor; TGF B; TGF-beta; TGF-ß; TGFbeta; TGFß; Transforming Growth Factor-Beta Family Gene; EtOH abuse; alcohol co-abuse; alcohol problem; ethanol abuse; hazardous alcohol use; problem alcohol use; problem drinking; problematic alcohol consumption; problematic alcohol use; Alcohol abuse; Liver Dysfunction; Apoptosis Pathway; Programmed Cell Death; Apoptosis; dosage; Organ; Area; Surface; Chronic; Phase; Cardiac Muscle Cells; Cardiocyte; Heart Muscle Cells; Heart myocyte; cardiomyocyte; Cardiac Myocytes; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; Funding; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Therapeutic Agents; Attenuated; attenuate; attenuates; Myocardial dysfunction; Myocardial depression; cardiac dysfunction; heart dysfunction; programs; Oral; cell type; Autocrine Communication; Autocrine Signaling; Paracrine Communication; Paracrine Signaling; coronary fibrosis; cardiac fibrosis; myocardial fibrosis; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Basic Science; Basic Research; Prevention; Pathogenesis; Modeling; drug development; alcohol abuse therapy; alcohol abuse treatment; alcohol treatment; preventing; prevent; small molecule; Dose; Preventive; Data; Apoptotic; Rodent Model; Small Business Technology Transfer Research; STTR; Process; Myocardial; Ventricular; Cardiac; Development; developmental; safety study; preclinical study; pre-clinical study; feeding; chronic EtOH drinking; chronic alcohol consumption; chronic alcohol drinking; chronic alcohol use; chronic ethanol consumption; chronic ethanol drinking; chronic ethanol ingestion; chronic alcohol ingestion; Prevention therapy; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; ethanol testing; alcohol testing; commercialization; FDA approved; effective treatment; effective therapy; Phase I Study; phase 1 study; phase II study; phase 2 study; Formulation; translation to humans; efficacy study; cardiac damage; heart damage; renal dysfunction; kidney dysfunction; Natural Compound; naturally occurring compound; manufacture
