Anti-LPS antibody for Pediatric Nonalcoholic Fatty Liver Disease

抗 LPS 抗体治疗小儿非酒精性脂肪肝

• 批准号: 9168600
• 负责人: MIRIAM B. VOS
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168600
• 关键词: Address; Adult; Adverse effects; Affect; Age; Alcoholic Hepatitis; Antibodies; Australia; Biopsy; Blood; Canada; Caring; Cattle; Child; Child health care; Childhood; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Colostrum; Controlled Clinical Trials; Data; Decision Making; Double-Blind Method; Effectiveness; Endotoxemia; Enrollment; Enzymes; Escherichia coli; Exposure to; FDA approved; Feces; Future; Goals; Health; Healthcare; Hepatic; Histology; Immune Response Genes; Immune response; Immunoglobulin G; Individual; Inflammation; Insulin Resistance; Letters; Life Style; Lipids; Lipopolysaccharides; Liver; Liver diseases; Measurement; Medical; Milk; Mission; Monitor; Mucous Membrane; Multicenter Trials; National Institute of Child Health and Human Development; Obesity; Participant; Patients; Permeability; Placebo Control; Placebos; Population; Positioning Attribute; Powder dose form; Quality of life; Randomized; Recruitment Activity; Regulatory T-Lymphocyte; Research Design; Research Personnel; Resolution; Ribosomal RNA; Risk; Role; Safety; Sample Size; Subgroup; System; Target Populations; Testing; Therapeutic; Traveler' s diarrhea; United States; United States National Institutes of Health; Universities; Vaccinated; blood lipid; chronic liver disease; cytokine; design; gut microbiome; improved; insulin sensitivity; liver inflammation; liver transplantation; medical food; member; metabolomics; microbial; microbiome; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel therapeutics; pathogenic bacteria; phase 1 study; phase 2 study; phase III trial; pregnant; prevent; primary outcome; response; secondary outcome; standard of care; transcriptomics; treatment strategy; treatment trial

Project Summary Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects 10-30% of children in the United States. NAFLD is surprisingly aggressive in children and there is currently no approved therapy for it. Because the onset of NAFLD is often in young children (8-12 years), any potential therapeutic for NAFLD will need to be almost risk-free. In this proposal, we seek to study IMM-124E, a medical product that was initially developed for traveler’s diarrhea and has been available over the counter in Australia for years. IMM-124E is a hyperimmune bovine colostrum manufactured by drying the cow’s first milk and packaging it into caplets. This hyperimmune “milk powder” is enriched with IgG against E. coli bacterial products (LPS) by vaccinating the pregnant cow. Because altered microbiome, increased gut permeability, and increased LPS have been shown to be important in the mechanism of NAFLD, IMM-124E has logical support for efficacy in NAFLD. Phase I studies in adults have shown improved insulin resistance, liver enzymes, and promotion of regulatory T-cells. This proposal is designed to test IMM-124E in a small phase II study in children with NAFLD in order to assess preliminary efficacy and safety endpoints and to improve understanding of the mechanisms. This will be accomplished through two aims in a 12 week double-blind, randomized, placebo-controlled clinical trial in children with NAFLD. Aim 1 will determine if 3 months of treatment with IMM-124E in combination with lifestyle changes (standard of care (SOC)) results in greater improvement in 1) hepatic lipid and inflammation, 2) insulin sensitivity, 3) blood lipids, in children with NAFLD, compared to placebo with SOC as well as monitor safety related endpoints. Aim 2 will define mechanisms of action-related endpoints including: stool microbiome, metabolomics, LPS and transcriptomics of innate immune response genes and correlate these with changes in clinical measurements. The proposal leverages state-of-the art platforms at Emory University including high throughput, high resolution metabolomics and established centers for microbiome and transcriptomics to accomplish the mechanism studies. Additionally, we have the clinical population to quickly enroll children into this trial. This proposal addresses the mission of the NIH NCCIH and NICHD by rigorously investigating a complementary treatment with the potential to improve health for large numbers of children. If successful, these studies would support designing a future large scale phase III trial. These studies will enhance our understanding of the role of the gut in pediatric NAFLD and if positive, will result in a low risk, low side effect, high yield therapeutic for pediatric NAFLD.

项目概要 非酒精性脂肪肝 (NAFLD) 是一种慢性肝病，影响美国 10-30% 的儿童 国家。 NAFLD 对儿童具有惊人的侵袭性，目前尚无批准的治疗方法。因为 NAFLD 的发病通常是幼儿（8-12 岁），因此任何潜在的 NAFLD 治疗方法都需要 几乎没有风险。在本提案中，我们寻求研究 IMM-124E，这是一种最初开发的医疗产品 用于治疗旅行者腹泻，多年来一直在澳大利亚非处方药销售。 IMM-124E 是一款 通过干燥牛初乳并将其包装成囊片而制成的超免疫牛初乳。这 超免疫“奶粉”通过接种疫苗富含针对大肠杆菌细菌产物 (LPS) 的 IgG 怀孕的母牛。因为微生物群的改变、肠道通透性的增加和脂多糖的增加已被证明 IMM-124E 在 NAFLD 的发病机制中发挥着重要作用，为 NAFLD 的疗效提供了逻辑支持。第一阶段研究 成人中的胰岛素抵抗、肝酶和调节性 T 细胞的促进得到改善。这 该提案旨在在 NAFLD 儿童的一项小型 II 期研究中测试 IMM-124E，以评估 初步疗效和安全性终点，并提高对机制的了解。这将是 通过一项为期 12 周的双盲、随机、安慰剂对照临床试验的两个目标来实现 患有 NAFLD 的儿童。目标 1 将确定 3 个月的 IMM-124E 治疗是否与 生活方式的改变（护理标准 (SOC)）可显着改善 1) 肝脂和炎症， 与安慰剂、SOC 和监测仪相比，NAFLD 儿童的 2) 胰岛素敏感性，3) 血脂 安全相关的终点。目标 2 将定义与行动相关的终点机制，包括：粪便微生物组、 先天免疫反应基因的代谢组学、LPS 和转录组学，并将这些与 临床测量。该提案利用了埃默里大学最先进的平台，包括高 通量、高分辨率代谢组学以及已建立的微生物组和转录组学中心 完成机理研究。此外，我们拥有临床人群，可以快速将儿童纳入 这次审判。该提案通过严格调查一个问题来体现 NIH NCCIH 和 NICHD 的使命。 补充治疗有可能改善大量儿童的健康。如果成功的话，这些 研究将支持设计未来的大规模 III 期试验。这些研究将加深我们的理解 肠道在儿科 NAFLD 中的作用，如果呈阳性，将导致低风险、低副作用、高产量 治疗小儿 NAFLD。