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: 7404944
• 负责人: STANISLAV I SVETLOV
• 金额: $ 42.25万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404944
• 关键词: Abdomen; Acetaminophen; Acute; Affect; Alcoholic Hepatitis; 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; Condition; Crush syndrome; Data; Data Analyses; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Drug Prescriptions; Drug or Chemical; Early Diagnosis; Emergency Situation; End Point; 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; Invasive; 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; Numbers; Organ failure; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathogenesis; Patient Monitoring; Patients; Pattern; Peptides; Performance; Pharmaceutical Preparations; Phase; Physiological reperfusion; Plasma; Play; Production; Proteins; Proteomics; Public Health; Quality Control; Range; 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 Funding Mechanisms; Small Business Innovation Research Grant; Source; Standards of Weights and Measures; Steatohepatitis; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Transaminases; Transplantation; Trauma; United States Food and Drug Administration; Validation; Viral; Viral hepatitis; Western Blotting; argininosuccinate synthase; assay development; commercialization; concept; 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; 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（由申请方提供）：各种形式的肝损伤导致的肝损伤和肝衰竭是美国和全球总体发病率和死亡率的重要来源。持续性肝损伤发生在病毒性肝炎、脂肪性肝病（脂肪性肝炎）、药物或酒精以及自身免疫性肝炎期间。临床病症很多，其中肝损伤是由复杂创伤引起的多器官衰竭的重要组成部分，所述复杂创伤包括冲击伤、感染性休克和肝移植后的移植物衰竭，通常导致患者死亡。血清ALT和AST的酶法测定，广泛用作“肝功能”小组的一部分，对肝脏既不敏感也不特异，不能评估肝损伤的程度或预测结果。如果肝脏损伤迫在眉睫，通常会使用组织活检进行诊断。这表明明确的临床需要用于早期检测肝损伤的非侵入性生物标志物，具有增强的诊断信息。我们建议继续开发新的肝脏特异性生物标志物，这些生物标志物易于在血清中检测，可用于肝损伤患者的早期诊断，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用于肝毒性的临床前研究。我们在大鼠肝损伤模型中鉴定了几种新的肝脏特异性生物标志物，其中乙酰氨基琥珀酸合酶（ASS）和肝雌激素磺基转移酶（EST-1）是最敏感的标志物，它们在血液中迅速积累，并与损伤的严重程度相关。在I期，开发了用于定量血清中ASS的原型SW ELISA，并且获得了充分的数据，证明与ALT/AST相比，在肝损伤的实验模型中具有更高的生物标志物灵敏度和特异性。此外，我们提供了概念验证数据，表明血清ASS在患有几种类型的肝脏疾病和肝损伤的人类患者中的诊断和预后价值。在第二阶段，将开发ASS和EST-1的即用型ELISA试剂盒，并在肝损伤和肝毒性大鼠模型的临床前研究中进行验证。将在质量保证条件下生产充足的试验组分（例如抗体和抗原）。我们将描述ASS和EST-1检测在患有各种类型肝脏疾病和肝损伤的人类患者中的诊断潜力。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、疾病进展和结局。将评估ASS/EST-1的准确性、敏感性、特异性和诊断/预后价值，并与ALT/AST进行比较。这些分析将用于支持向FDA提交的IDE前申请，以确认这些检测试剂盒作为诊断工具并进一步商业化。该II期项目的可交付成果将是两种肝损伤生物标志物的质量保证ELISA检测，以及支持使用生物标志物作为辅助诊断肝损伤和监测肝毒性程度的工具的临床数据，远远超出ALT/AST测量获得的信息。 公共卫生相关性：肝脏健康是人类福祉的重要组成部分。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病，包括病毒性肝炎，酒精性肝病或肝癌，这些疾病经常导致肝功能衰竭，需要进行肝移植。此外，越来越多的处方药，如降胆固醇药物和非处方药，包括对乙酰氨基酚，可能会导致肝毒性，从而需要进行医学肝功能检查。在过去的30年里，两种酶，血清ALT和AST已被用于肝功能面板，以评估肝脏健康。然而，ALT/AST在检测轻度损伤、评估损伤程度或预测预后方面既不敏感也不特异。Banyan Biomarkers正在开发预测性生物测定法，如ASS和EST-1，可以帮助早期确定患有治疗药物或环境毒素肝毒性的患者的肝损伤。这些检测将提供一种新的诊断/预后工具，并作为“安全性生物标志物”。”根据FDA。