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) 是乙醇诱发的心脏病最常见的形式 酒精剂量依赖性地诱发 ACM，其特征是心肌收缩逐渐减少 慢性酒精会导致收缩力和心室扩张，最终导致心力衰竭。 食用会导致心肌细胞死亡、心脏炎症和心脏纤维化，目前尚无发现。 FDA 批准的 ACM 疗法该项目的长期目标是推进大黄素（一种小分子）的发展。 具有抗炎、抗细胞凋亡和抗纤维化活性的天然化合物，用于预防 ACM 或 我们在基础科学和早期发现方面生成了大量的背景数据。 支持大黄素作为 ACM 新型疗法的阶段包括：1) TGFβ 信号传导是主要的基础 酒精诱发的心脏纤维化的机制，这是 ACM 发病机制的关键组成部分，2) 大黄素是多种细胞类型中 TGFβ 经典和非经典信号传导的有效抑制剂，3) 大黄素的药代动力学 (PK) 和出色的安全性已在小鼠模型中得到检验，并且 4) 在非 有毒口服剂量，大黄素可有效改善与多柔比星相关的心脏纤维化和功能障碍，阿霉素是一种 病理学与 ACM 类似。此外，我们的初步数据表明大黄素可减轻酒精诱导的症状。 我们建议进一步测试中枢心肌细胞活力的丧失和心脏成纤维细胞的活化。 假设大黄素可以开发为安全有效的 ACM 预防和/或治疗剂。 在此 1 期 STTR 申请中，我们建议检查大黄素在慢性病中的 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 目的SA1。测试饮酒是否影响大黄素代谢并评估安全性和有效性。 大黄素在小鼠模型中改善 ACM 的作用 检测大黄素在小鼠模型中的 PK、安全性和有效性。 在预防和治疗环境中减少酒精喂养大鼠的心脏纤维化和心脏功能障碍。 SA3.进行大黄素在猪体内的PK和安全性研究，寻找可以达到有效效果的安全剂量范围 到 STTR 第一阶段申请的资助期结束时，我们将 可能将大黄素推向药物开发的下一阶段：支持 IND 的临床前研究。 进行/不进行的决定包括： 1) 如果大黄素没有夸大酒精引起的小鼠和大鼠的毒性， 特别是肝脏毒性；2）大黄素是否对改善小鼠和大鼠的 ACM 具有显着功效； 3) 如果在猪中确定了适当的安全剂量，则可以将其推断到人类身上 如果回答了上述问题。 三个问题是肯定的，将做出进一步推进大黄素开发进程的决定，以及 将提交 II 期申请以进行支持 IND 的临床前研究，包括 1) 安全性和 在 GLP 环境下对猪 ACM 模型进行功效研究，以及 2) 大黄素的配方和 cGMP 生产 供人类使用的胶囊。