Developing natural compound emodin as a therapy for alcoholic cardiomyopathy

开发天然化合物大黄素治疗酒精性心肌病

• 批准号: 10597858
• 负责人: WAYNE E CARVER
• 金额: $ 45.68万
• 依托单位: ACEPRE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597858
• 关键词: Alcohol abuse; Alcohol consumption; Alcoholic Cardiomyopathy; Alcohols; Anatomy; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Area; Arrhythmia; Attenuated; Autocrine Communication; Basic Science; Blood; Body Weight; Cardiac; Cardiac Myocytes; Cessation of life; Chronic; Cyclic GMP; Data; Data Reporting; Development; Dilatation - action; Disease; Dose; Doxorubicin; Drug Kinetics; Emodin; Ethanol; FDA approved; Family suidae; Fibroblasts; Formulation; Functional disorder; Funding; Future; Goals; Heart; Heart failure; Hepatotoxicity; Human; Inbred BALB C Mice; Literature; Liver; Liver Dysfunction; Malignant Neoplasms; Metabolism; Modeling; Mus; Myocardial; Myocardial dysfunction; Myocarditis; Natural Compound; Necrosis; Oral; Organ; Paracrine Communication; Pathogenesis; Pathology; Pharmaceutical Preparations; Phase; Prevention; Prevention therapy; Preventive; Process; Rattus; Rodent Model; Safety; Signal Transduction; Small Business Technology Transfer Research; Surface; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transforming Growth Factor beta; Ventricular; Wistar Rats; alcohol abuse therapy; alcohol testing; capsule; cell type; chronic alcohol ingestion; commercialization; coronary fibrosis; dosage; drug development; effective therapy; efficacy study; feeding; heart damage; inhibitor; kidney dysfunction; manufacture; mouse model; novel therapeutics; phase 1 study; phase 2 study; preclinical study; prevent; programs; safety study; small molecule; translation to humans

Project Summary: 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) TGFβ 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 TGFβ 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.

项目概述：酒精性心肌病（ACM）是最常见的酒精性心脏疾病