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.

项目摘要：酒精性心肌病（ACM）是乙醇引起的心脏最普遍的形式 损害。酒精剂量依赖性地诱导ACM，其特征是心肌减少 收缩和心室扩张，最终导致心力衰竭。在细胞水平，慢性酒精 消耗导致心肌细胞死亡，心脏感染和心脏纤维化。目前没有 FDA批准的ACM疗法。该项目的长期目标是促进小型蛋白，这是一个小分子 具有抗炎，抗凋亡和抗纤维化活性的天然化合物，用于预防ACM或 治疗。我们在基础科学和早期发现中产生了强大的背景数据 支持Emodin作为ACM的新疗法的阶段，包括：1）TGFβ信号是主要的基础 导致酒精诱导心脏纤维化的机制，心脏纤维化是ACM发病机理的关键组成部分，2） Emodin是多种细胞类型中TGFβ规范和非典型信号传导的有效抑制剂，3） 在鼠模型中已经检查了药代动力学（PK）和巨素的出色安全性，4）在非 - 有毒的口服剂量，Emodin有效地改善了与阿霉素相关的心脏纤维化和功能障碍 病理类似于ACM。此外，我们的初步数据说明了Emodin减弱了酒精诱导的 心肌细胞生存能力的丧失和心脏成纤维细胞的激活。我们建议进一步测试中央 假设巨素可以作为ACM的安全有效的预防和/或治疗剂开发。 在此阶段1 STTR应用中，我们建议检查Emodin在慢性的PK，安全性和有效性 饮酒啮齿动物模型并在以下三个特定的猪中进行PK和毒性研究 目标。 SA1。测试饮酒是否影响卵素代谢并评估安全性和效率 在小鼠模型中改善ACM中的EMODIN。 SA2。检查EMODIN的PK，安全性和有效性 在预防和治疗环境中，降低酒精喂养大鼠的心脏纤维化和心脏功能障碍。 SA3.进行PK和对猪Emodin的安全性研究，并找到可以有效的安全剂量范围 血红素浓度。在此STTR 1阶段申请的资金期结束时，我们将 里程碑可能会将巨素转移到下一阶段的药物开发：促进临床前研究。 对于GO/NO-GO的决定包括：1）如果Emodin不会夸大酒精引起的小鼠和大鼠的毒性， 特别是肝毒性； 2）如果在小鼠和大鼠的改善ACM中具有明显的EMODIN效率；和 3）如果在可以推断到人类的猪中鉴定出适当的安全剂量。如果回答以上 三个问题是积极的，将做出决定，以进一步促进大莫蛋白的发展过程，一个 第二阶段的申请将提交以进行授予临床前研究，包括1）安全性和 在GLP设置中的PIG ACM模型中的效率研究，以及2）EMODIN的配方和CGMP制造 用于人类使用的胶囊。