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.

项目摘要 非酒精性脂肪肝疾病（NAFLD）是一种慢性肝病，影响了美国联合儿童的10-30％ 国家。 NAFLD在儿童中令人惊讶地具有侵略性，目前尚无批准的疗法。因为 NAFLD的发作通常在幼儿（8-12岁），任何潜在的NAFLD疗法都需要是 几乎没有风险。在此提案中，我们试图研究IMM-124E，这是一种最初开发的医学产品 对于旅行者的腹泻，多年来一直在澳大利亚的柜台上使用。 IMM-124E是a 通过将牛的第一种牛奶干燥并将其包装到胶囊中，生产的超免疫牛初乳。这 通过接种疫苗接种，对大肠杆菌细菌产物（LPS）富含IgG的高免疫“奶粉” 怀孕的牛。由于微生物组改变，肠道渗透性增加和LP的增加已显示为 在NAFLD的机理中要重要，IMM-124E具有逻辑支持NAFLD的效率。第一阶段的研究 在成年人中，已经显示出改善的胰岛素抵抗，肝酶和调节性T细胞的促进。这 建议旨在在NAFLD儿童的II阶段研究中测试IMM-124E，以评估 初步效率和安全终点，并提高对机制的理解。这将是 在12周的双盲，随机，安慰剂对照的临床试验中通过两个目标完成 Nafld的孩子。 AIM 1将确定IMM-124E治疗3个月是否与 生活方式的改变（护理标准（SOC））在1）肝脂质和炎症中会得到更大的改善， 2）胰岛素敏感性，3）NAFLD儿童的血脂，与SOC和监测器相比 与安全有关的终点。 AIM 2将定义与动作相关终点的机制，包括：粪便微生物组， 先天免疫反应基因的代谢组学，LP和转录组学，并将其与变化相关 临床测量。该提案利用埃默里大学（Emory University）的最先进平台 吞吐量，高分辨率代谢组学和微生物组和转录组学中心 完成机制研究。此外，我们还有临床人群迅速让儿童加入 这个试验。该提案通过严格调查了NIH NCCIH和NICHD的使命 完全治疗，有可能改善大量儿童的健康。如果成功，这些 研究将支持设计未来的大规模III期试验。这些研究将增强我们的理解 肠道在小儿NAFLD中的作用，如果阳性，将导致较低的风险，低副作用，高产量 小儿NAFLD的治疗性。