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

基本信息

批准号：
8012889
负责人：
STANISLAV I SVETLOV
金额：
$ 4.59万
依托单位：
BANYAN BIOMARKERS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8012889
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

项目摘要

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）：各种形式的肝损伤导致的肝损伤和衰竭是美国和全世界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。临床情况多种多样，其中肝损伤是复杂创伤引起的多器官衰竭的重要组成部分，包括爆炸伤、感染性休克和肝移植后移植失败，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”组的一部分，对肝脏既不敏感也不具有特异性，并且不能评估肝损伤的程度或预测结果。如果肝损伤迫在眉睫，通常使用组织活检进行诊断。这表明临床上明确需要非侵入性生物标志物来早期检测肝损伤并提供增强的诊断信息。我们在此建议继续开发新型肝脏特异性生物标志物，这些生物标志物在血清中很容易检测到，可用于肝损伤患者的早期诊断，并有助于监测患者在药物治疗期间潜在的肝毒性。我们的生物标志物还可用于肝毒性的临床前研究。我们在大鼠肝损伤模型中发现了几种新型肝脏特异性生物标志物，其中精氨酸琥珀酸合酶（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。在第一阶段，开发了用于量化血清中 ASS 的原型 SW ELISA，并获得了足够的数据，证明与 ALT/AST 相比，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，我们还提供了概念验证数据，表明血清 ASS 对患有多种类型肝病和肝损伤的人类患者的诊断和预后价值。在第二阶段，将开发用于 ASS 和 EST-1 的即用型 ELISA 试剂盒，并在大鼠肝损伤和肝毒性模型的临床前研究中进行验证。将在质量有保证的条件下生产充足的检测成分（例如抗体和抗原）。我们将描述 ASS 和 EST-1 检测对患有各种类型肝病和肝损伤的人类患者的诊断潜力。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、疾病进展和结果。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 提交预 IDE 申请，以验证这些检测方法作为诊断工具的有效性并进一步商业化。该二期项目的成果将是对两种肝损伤生物标志物进行有质量保证的 ELISA 测定，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，这些数据远远超出从ALT/AST 测量。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、药物或过量酒精都会损害肝脏并影响其功能。据估计，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衰竭并需要肝移植。此外，越来越多的处方药（例如降胆固醇药）和非处方药（包括对乙酰氨基酚）可能会导致肝毒性，因此需要进行肝功能检查。在过去的 30 年里，血清 ALT 和 AST 两种酶已被用于肝功能检测，以评估肝脏健康状况。然而，ALT/AST 对于检测轻度损伤、评估损伤程度或预测结果既不敏感也不特异。 Banyan Biomarkers 正在开发 ASS 和 EST-1 等预测性生物测定法，可以帮助在因治疗药物或环境毒素而遭受肝毒性的患者中及早确定肝脏损伤。这些测定将提供新颖的诊断/预后工具并作为“安全生物标志物”。根据 FDA 的数据。