TREAT-Mayo

描述（由申请人提供）：由于缺乏有效的治疗方法，AH（AH）是发病和死亡的主要原因。如RFA-AA-12-007所述，平移 需要研究与AH相关的新机制和合适的药理学药物。该申请是组成联盟（转化研究和不断发展的酒精性肝炎治疗; TREAT）的三个申请之一，包括印第安纳州大学、弗吉尼亚联邦大学和马约诊所。TREAT联盟的总体目标是进行以患者为导向的转化研究，以发现和测试治疗AH的新的靶点。这一特定的ESTA梅奥应用程序将集中在扩展最近的研究，揭示了半胱天冬酶依赖的细胞死亡途径作为AH的致病元凶的关键作用。在本提案中，我们将检验中心假设，即新型半胱天冬酶抑制剂emricasan通过抑制肝细胞凋亡和无菌性坏死的机制对AH患者安全有效。我们还将通过招募患者进行注释良好的登记，并通过提供与肝损伤、炎症和细胞死亡广泛相关的人血清和肝组织分析的机制资源，支持TREAT联盟的更广泛目标。因此，本申请的具体目的是：1）开发AH患者的纵向观察队列。我们将开发一项前瞻性多中心登记研究，纳入具有良好特征的AH和适当对照的患者，作为进行人体治疗（如目标2所述）和新型机制（如目标3所述）研究的临床和生物样本基础。2)检验4周emricasan给药将改善AH患者生存率的假设。我们将进行一项早期随机化、设盲、安慰剂对照研究，该研究将纳入一个特殊的重度AH患者人群，这些患者根据特定的禁忌症不适合接受皮质类固醇治疗。3)检验细胞凋亡和无菌性坏死促进AH发展且为恩利卡生致病靶点的假设。我们将测量细胞凋亡和无菌坏死的血清和肝组织标志物，以了解这些分子过程如何导致人类AH的肝损伤和炎症。因此，本研究由一组在临床AH和基础性肝损伤方面具有丰富经验的研究人员提交，将确定一种新型创新疗法（半胱天冬酶抑制剂emricasan）在AH患者中的安全性和潜在疗效。此外，提出的机制分析将阐明不同的细胞死亡途径如何导致人类AH，以及半胱天冬酶抑制如何消除这些途径，从而抑制AH患者的肝损伤和炎症。我们在患者招募试验方面的记录和在肝损伤途径方面的广泛资源也将为该联盟的更广泛成功提供关键组成部分。总的来说，这项应用将为我们进一步了解AH的破坏性状况迈出重要一步。

DESCRIPTION (provided by applicant): AH (AH) is a major cause of morbidity and mortality due to a lack of effective treatments for this condition. As stated in RFA-AA-12-007, translational investigations are needed on new mechanisms and suitable pharmacological agents relevant to AH. This application is one of three that comprise a consortium (Translational Research and Evolving Alcoholic Hepatitis Treatment; TREAT) and include Indiana University, Virginia Commonwealth University, and Mayo Clinic. The Overall goals of the TREAT consortium are to perform patient oriented translational studies that will uncover and test new pharmacologically relevant targets for the treatment of AH. This specific TREAT-Mayo application will focus on expansion of recent studies that have revealed a key role for caspase dependent cell death pathways as a pathogenic culprit in AH. In this proposal, we will test the Central Hypothesis that the novel caspase inhibitor emricasan is safe and effective in patients with AH through a mechanism involving inhibition of hepatocellular apoptosis and sterile necrosis. We will also support the broader goals of the TREAT consortium by recruiting patients for a well annotated registry and by providing a mechanistic resource for human serum and liver tissue analyses that are broadly pertinent to liver injury, inflammation, and cell death. Thus, the Specific Aims of thi application are to: 1) Develop longitudinal observational cohort of patients with AH. We will develop a prospective multicenter registry of patients with well characterized AH and suitable controls that serves as the clinical and biosample based foundation for conducting human therapeutic (as described in Aim 2) and novel mechanistic (as described in Aim 3) studies. 2) Test the hypothesis that 4-week emricasan administration will improve survival in patients with AH. We will conduct an early phase randomized, blinded, placebo controlled study, which will include a special population of patients with severe AH who are not otherwise candidates for corticosteroid therapy based on specific contraindications. 3) Test the hypothesis that apoptosis and sterile necrosis contribute to development of AH and are pathogenic targets of emricasan. We will measure serum and liver tissue markers of both apoptosis and sterile necrosis to inform our understanding of how these molecular processes contribute to liver injury and inflammation in human AH. Thus, this study, submitted by a group of investigators with extensive experience in clinical AH and basic liver injury, will determine the safety and potential efficacy of a novel and innovative therapy, the caspase inhibitor emricasan, in patients with AH. Additionally, the proposed mechanistic analyses will elucidate how distinct cell death pathways contribute to human AH and how caspase inhibition abrogates these pathways thereby inhibiting liver injury and inflammation in patients with AH. Our track record in patient recruitment trials and expansive resources in liver injury pathways will also provide key components for the broader success of this consortium. In total, this application will provide a major step in advancing our understanding of the devastating condition of AH.