TREAT-VCU

描述(由申请人提供)：根据RFA-AA-12-007，成立了“转化研究和进化酒精性肝炎治疗”(THEAT)联合体。该联盟由印第安纳大学(IU)、梅奥诊所(MC)和弗吉尼亚联邦大学(VCU)组成。治疗联盟的主要目标是与酒精性肝炎(AH)的基础科学家密切合作，开展以患者为导向的研究，并加快新发现的翻译。治疗联盟的三个主要目标是：(1)进行一项前瞻性的多中心观察性研究，以建立一个具有良好特征的登记和生物样本库，并对AH的自然历史有更新的见解。2.利用三种针对AH可能的机制的新药进行三个阶段的2a“概念验证”试验；以及(3)利用在特定目标1和2下收集的样本，更好地了解人类AH的病理生理机制和治疗反应的预测因素。所有中心都将为特定目标1做出贡献。Treat-VCU将侧重于肠道完整性、内毒素血症、肠道微生物区系、二十烷类化合物的代谢组学和作用，特别是脂氧合酶。具体目标2提出了一项2a期“概念验证”安慰剂对照的剂量范围研究(IMM 124-E)(富含免疫球蛋白G抗脂多糖(LPS)的牛初乳)，用于重度AH患者。重度急性胰腺炎患者将接受标准护理和类固醇治疗。受试者在开始服用类固醇时将被随机接受研究药物或安慰剂。受试者将被监测研究药物的治疗成败、安全性、耐受性和有效性。Treat-VCU的具体目标3是确定全身性脂氧合酶激活(LOX)作为AH严重程度的驱动因素的作用。我们将测试这一假说，即肠道微生物衍生的代谢物激活循环巨噬细胞产生促炎LOX，从而激活驱动严重AH表型的途径。我们将在重度急性酒精中毒、轻度急性酒精中毒、无急性酒精中毒的重度饮酒者和匹配的非酒精对照组的受试者中，对微生物组-元基因组和系统二十聚糖组进行详细的表征，并进一步建立它们与肝脏转录组的关系。预计拟议的研究将展示对AH自然历史的新见解，新疗法作为概念的证据，并确定新的干预和药物开发目标，朝着加快新发现的转化的目标更接近NIAAA的优先事项。

DESCRIPTION (provided by applicant): The "Translational Research and Evolving Alcoholic-hepatitis Treatment" (TREAT) consortium was established in response to the RFA-AA-12-007. This consortium comprises of Indiana University (IU), Mayo Clinic (MC) and the Virginia Commonwealth University (VCU). The main objective of TREAT consortium is to perform patient oriented research in close collaboration with basic scientists in alcoholic hepatitis (AH) and expedite the translation of emerging findings. The three overarching aims of TREAT consortium are: (1) to perform a prospective, multicenter observational study leading to a well characterized registry and bio-sample repository together with newer insights into the natural history of AH~ (2) to perform three phase 2a "proof of concept" trials with three novel agents targeting putative mechanisms of AH, and (3) to better understand the mechanisms involved in the pathophysiology of human AH and predictors of response to therapy utilizing samples collected under specific aims 1 and 2. All centers will contribute for specific aim 1. The TREAT-VCU will focus on the role of gut integrity, endotoxemia, gut microbiota, metabolomics and role of eicosanoids specifically lipoxygenases. Specific aim 2 proposes a phase 2a "proof of concept" placebo- controlled, dose-ranging study of Imm 124-E (bovine colostrum enriched with IgG anti-lipopolysaccharide (LPS)) in subjects with severe AH. Subjects with severe AH will receive standard of care and steroids when indicated. The subjects when starting steroids will be randomized to receive the study drug or placebo. The subjects will be monitored to treatment success and failure, safety, tolerability and efficacy of the study drug. The specific aim 3 of TREAT-VCU is to define the role of systemic activation of lipoxygenases (LOX) as a driver of the severity of AH. We will test the hypothesis that intestinal microbiome-derived metabolites activate circulating macrophages to produce pro-inflammatory LOX that activate pathways that drive the phenotype of severe AH. We will perform detailed characterization of the microbiome-metagenome and the systemic eicosanoid profile and further establish their relationship to the hepatic transcriptome using a "systems biology" approach in subjects with severe AH, mild AH, heavy drinkers without AH and matched non-alcoholic controls. The proposed studies are expected to demonstrate new insights into the natural history of AH, novel therapies as proof of concept and identify newer targets for intervention and drug development moving closer to the goal of accelerating the translation of newer findings in direct alignment with the priorities of NIAAA.