Developing natural compound emodin as a therapy for alcoholic cardiomyopathy

酒精性心肌病（ACM）是最常见的乙醇诱导的心脏病 损害酒精剂量依赖性地诱导ACM，其特征在于心肌细胞的进行性减少。 收缩性和心室扩张，最终导致心力衰竭。在细胞水平上，慢性酒精 消耗导致心肌细胞死亡、心脏炎症和心脏纤维化。目前没有 FDA批准的ACM治疗方法。该项目的长期目标是推进大黄素，一种小分子 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 治疗我们已经在基础科学和早期发现方面产生了大量的背景数据 支持大黄素作为ACM的新疗法的阶段包括：1）TGFβ信号传导是ACM的主要基础 负责酒精诱导的心脏纤维化的机制，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。 已经在鼠模型中检查了大黄素的药代动力学（PK）和优异的安全性，以及4）在非 口服毒性剂量，大黄素有效地改善心脏纤维化和功能障碍与阿霉素， 病理学与ACM相似。此外，我们的初步数据表明，大黄素减弱酒精诱导的 心肌细胞活力丧失和心脏成纤维细胞活化。我们建议进一步测试中央 大黄素可作为一种安全有效的ACM预防和/或治疗药物。 在这项1期STTR申请中，我们建议检查大黄素在慢性炎症中的PK、安全性和疗效。 酒精消耗啮齿动物模型，并在猪中进行以下三个特定的PK和毒性研究 目标。SA 1.检测饮酒对大黄素代谢的影响，评价其安全性和有效性 大黄素改善小鼠ACM的作用。SA 2.为了检查大黄素的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。 SA 3.进行大黄素在猪体内的药代动力学和安全性研究，寻找一个安全的剂量范围， 血大黄素浓度在短期信托基金第一阶段申请的资助期结束前，我们将 可能推动大黄素进入药物开发的下一阶段：IND使能临床前研究。里程碑 对于进行/不进行的决定包括：1）如果大黄素在小鼠和大鼠中不加重酒精诱导的毒性， 特别是肝毒性; 2）大黄素是否在改善小鼠和大鼠中的ACM中具有显著功效;以及 3)如果在猪身上确定了适当的安全剂量，可以外推到人类身上。如果回答上述问题， 三个问题是积极的，将决定进一步发展大黄素的进程， 将提交II期申请，以进行IND使能临床前研究，包括1）安全性和 GLP环境中猪ACM模型的功效研究，以及2）大黄素的制剂和cGMP生产 人类使用的胶囊。

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.