Novel diagnostic and safety biomarkers of liver injury and hepatotoxicity

肝损伤和肝毒性的新型诊断和安全生物标志物

• 批准号: 7868731
• 负责人: STANISLAV I SVETLOV
• 金额: $ 3.04万
• 依托单位: BANYAN BIOMARKERS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7868731
• 关键词: Abdomen; Acetaminophen; Acute; Affect; Alcoholic Liver Diseases; Alcohols; American; Animal Experiments; Animals; Antibodies; Antigens; Autoimmune Hepatitis; Autoimmune Process; Biliary; Biological; Biological Assay; Biological Markers; Biopsy; Blast Injuries; Blood; Blood Circulation; Carbon Tetrachloride; Cause of Death; Cessation of life; Cholesterol; Chronic; Clinical; Clinical Data; Clinical Research; Collection; Complex; Crush syndrome; Data; Data Analyses; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Drug Prescriptions; Drug or Chemical; Early Diagnosis; Emergency Situation; Ensure; Enzyme-Linked Immunosorbent Assay; Enzymes; Estrone sulfotransferase; Ethanol toxicity; Evaluation; Experimental Models; Expressed Sequence Tags; Failure; Fatty Liver; Goals; Graft Rejection; Guidelines; Half-Life; Health; Hepatic; Hepatitis; Hepatitis C; Hepatobiliary; Hepatocellular Damage; Hepatotoxicity; Human; Human Anti-Mouse Antibody; Human Resources; Injury; Laboratories; Lead; Link; Liquid substance; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Measurement; Medical; Military Personnel; Modeling; Molecular; Monitor; Morbidity - disease rate; Multiple Organ Failure; Non-Prescription Drugs; Organ failure; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathogenesis; Patient Monitoring; Patients; Pattern; Peptides; Performance; Pharmaceutical Preparations; Phase; Plasma; Play; Production; Proteins; Proteomics; Quality Control; Rattus; Reagent; Recombinant Antibody; Recombinants; Recovery; Recurrence; Reperfusion Injury; Reperfusion Therapy; Reproducibility; Resolution; Role; Safety; Sampling; Sensitivity and Specificity; Sepsis; Septic Shock; Serological; Serum; Severities; Small Business Innovation Research Grant; Source; Steatohepatitis; Surrogate Markers; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Transaminases; Transplantation; Trauma; Validation; Viral; Viral hepatitis; Western Blotting; argininosuccinate synthase; assay development; commercialization; design; ecstasy; environmental chemical; follow-up; graft failure; hepatotoxin; human subject; immunogenic; injured; innovation; liver biopsy; liver function; liver ischemia; liver transplantation; mortality; non-alcoholic fatty liver; novel; novel diagnostics; pathogen; polyclonal antibody; pre-clinical; preclinical study; prognostic; prototype; public health relevance; research and development; response; sample collection; tool

DESCRIPTION (provided by applicant): Liver damage and failure due to various forms of hepatic injury is a significant source of overall morbidity and mortality in the US and worldwide. Persistent hepatic injury occurs during viral hepatitis, fatty liver disease (steatohepatitis), drug or alcohol and autoimmune induced hepatitis. Clinical conditions are numerous where hepatic injury is a vital component of multi-organ failure caused by complex trauma including blast injury, septic shock, and graft failure after liver transplantation often leading to death of the patient. Enzymatic assays of serum ALT and AST, widely used as part of a `hepatic function' panel, are neither sensitive nor particularity specific to the liver and do not assess the magnitude of liver injury or predict outcome. If liver damage is imminent, tissue biopsies are routinely used for diagnosis. This indicates an explicit clinical need for non-invasive biomarkers for early detection of liver injury with enhanced diagnostic information. We propose here the continuation of the development of novel liver specific biomarkers which are easily detected in serum and can be used for early diagnosis of patients with liver injury and aid in monitoring of potential liver toxicity in patients during drug treatment. Our biomarkers can also be used in preclinical studies of hepatotoxicity. We identified several novel liver-specific biomarkers in rat models of hepatic injury with the argininosuccinate synthase (ASS) and hepatic estrogen sulfotransferases (EST-1) being the most sensitive markers which rapidly accumulated in blood and correlated with the severity of damage. In Phase I, a prototype SW ELISA for quantifying ASS in serum was developed, and sufficient data were obtained demonstrating the greater biomarker sensitivity and specificity in experimental models of liver injury compared to ALT/AST. Also, we provided the proof-of-concept data indicating the diagnostic and prognostic value of serum ASS in human patients with several types of liver diseases and hepatic injury. In Phase II, a ready-to-use ELISAs Kits for ASS and EST-1 will be developed and validated in preclinical studies in rat models of liver injury and hepatotoxicity. Sufficient supplies of the assay components (e.g. antibodies and antigens) will be produced under quality assured conditions. We will characterize the diagnostic potential of ASS and EST-1 assays in human patients with various types of liver diseases and hepatic injury. The biomarker levels will be that will be correlated with clinical data including liver biopsy, serological and laboratory data with an emphasis on hepatic injury severity, disease progression and outcome. The accuracy, sensitivity, specificity and diagnostic/prognostic values of ASS/EST-1 will be assessed and compared with ALT/AST. These analyses will be used to support a pre-IDE application to the FDA for validation of these assays as diagnostic tools and further commercialization. The deliverables of this Phase II project will be quality assured ELISA assays for two liver injury biomarkers, and clinical data supporting the use of the biomarkers as tools for aid in the diagnosis of liver injury and monitor the magnitude of liver toxicity far beyond information obtained from ALT/AST measurements. PUBLIC HEALTH RELEVANCE: Liver health is a major component of human wellbeing. Many environmental chemicals, pathogens, drugs or excessive alcohol can harm the liver and affect its function. An estimated 5.5 million Americans have chronic liver diseases, including viral hepatitis, alcoholic liver disease or hepatic cancer, which frequently lead to liver failure and requires liver transplantation. Moreover, increasing numbers of prescription drugs such as cholesterol-lowering drugs and over-the-counter medications, including acetaminophen, can potentially cause liver toxicity and, thereby, require medical liver function checks. For the last 30 years, two enzymes, serum ALT and AST have been used in hepatic function panels to assess liver health. However, ALT/AST are neither sensitive nor specific to detect mild injure, assess magnitude of damage or predict outcome. Banyan Biomarkers is developing predictive bioassays such as ASS and EST-1 that can help determine liver insults early on in patients that suffer from liver toxicity from therapeutic drugs or environmental toxins. These assays will provide a novel diagnostic/prognostic tools and serve as "safety biomarkers." according to the FDA.

描述（由申请人提供）：各种形式的肝损伤引起的肝损害和失败是美国和全球总体发病率和死亡率的重要来源。在病毒肝炎，脂肪肝病（脂肪性肝炎），药物或酒精和自身免疫性诱发肝炎期间，持续性肝损伤发生。临床状况是众多，其中肝损伤是由复杂的创伤引起的多器官衰竭的重要组成部分，包括爆炸损伤，化粪池休克和肝移植后的移植失败，通常导致患者死亡。血清ALT和AST的酶测定，广泛用作肝功能面板的一部分，既不是敏感的也不是肝脏特有的，也不评估肝损伤的大小或预测结果。如果肝脏损害迫在眉睫，组织活检通常用于诊断。这表明对非侵入性生物标志物的明确临床需求通过增强的诊断信息提前检测到肝损伤。我们在这里提出，在血清中很容易检测到新型肝脏特异性生物标志物的发展，可用于早期诊断肝损伤患者，并有助于监测药物治疗期间患者的潜在肝毒性。我们的生物标志物也可以用于肝毒性的临床前研究。我们在肝损伤的大鼠模型中鉴定了几种新型肝脏特异性生物标志物，与精氨酸偶联合酶（ASS）和肝脏雌激素硫代磺基转移酶（EST-1）是最敏感的标记物，是在血液中迅速积累并与损害严重程度相关的最敏感的标记。在第一阶段，开发了用于量化血清中屁股的原型SW ELISA，并获得了足够的数据，证明了与ALT/AST相比，在肝损伤实验模型中，生物标志物的敏感性和特异性更高。此外，我们提供了概念验证数据，表明血清屁股在患有多种类型的肝病和肝损伤的人类患者中的诊断和预后价值。在II阶段，将在大鼠肝损伤和肝毒性的大鼠模型中开发和验证用于ASS和EST-1的现成ELISA套件。在质量保证的条件下，将产生足够的测定成分供应（例如抗体和抗原）。我们将表征患有各种类型的肝病和肝损伤的人类患者ASS和EST-1分析的诊断潜力。生物标志物水平将与临床数据相关，包括肝活检，血清学和实验室数据，重点是肝损伤严重程度，疾病进展和预后。将评估ASS/EST-1的准确性，灵敏度，特异性和诊断/预后值，并与Alt/AST进行比较。这些分析将用于支持对FDA的IDE申请，以验证这些分析作为诊断工具和进一步的商业化。该第二阶段项目的可交付成果将是对两种肝损伤生物标志物的ELISA分析的质量，以及支持使用生物标志物作为帮助诊断肝损伤的工具的临床数据，并监测远远超出了从ALT/AST测量的信息所获得的信息。 公共卫生相关性：肝脏健康是人类健康的主要组成部分。许多环境化学物质，病原体，药物或过量酒精会损害肝脏并影响其功能。估计有550万美国人患有慢性肝疾病，包括病毒肝炎，酒精性肝病或肝癌，这经常导致肝衰竭，需要肝移植。此外，越来越多的处方药，例如降低胆固醇的药物和包括对乙酰氨基酚在内的非处方药，可能会导致肝毒性，从而需要医疗肝功能检查。在过去的30年中，在肝功能面板中使用了两种酶，血清ALT和AST来评估肝脏健康。但是，ALT/AST既不敏感也不具体检测轻度伤害，评估损害的幅度或预测结果。 Banyan生物标志物正在开发预测性生物测定，例如ASS和EST-1，可以帮助确定患有治疗药物或环境毒素的肝脏毒性的患者的肝脏损伤。这些测定将提供一种新颖的诊断/预后工具，并用作“安全生物标志物”。根据FDA。