Noninvasive urinary monitoring of NASH by activity-based nanosensors

通过基于活动的纳米传感器对 NASH 进行无创尿液监测

• 批准号: 9464712
• 负责人: Eric Kai Huang
• 金额: $ 22.47万
• 依托单位: GLYMPSE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9464712
• 关键词: Adoption; Animal Model; Architecture; Benchmarking; Biopsy; Body Weight decreased; Canis familiaris; Caring; Cessation of life; Characteristics; Choline; Cirrhosis; Clinical; Clinical Trials; Collagen; Data; Decision Making; Detection; Development; Diagnosis; Diagnostic; Diet; Disease Progression; Disease regression; Dose; Drug Costs; Drug Kinetics; Enzyme Kinetics; Enzymes; Epidemic; Family; Fatty Liver; Fibrosis; Formulation; Gelatinase A; Generations; Gold; Health Care Costs; Healthcare Systems; Hemorrhage; Hepatic; Hepatitis C; High Fat Diet; Histologic; Histology; Hospitalization; Human; In Vitro; Inflammation; Injectable; Life; Link; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Mass Spectrum Analysis; Matrix Metalloproteinases; Measurable; Microscopic; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Obesity; Outcome; Pain; Patient Care; Patients; Peptide Hydrolases; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; Polymers; Population; Preparation; Prevalence; Primary carcinoma of the liver cells; Procedures; Progressive Disease; Property; Publishing; Reporting; Risk; Rodent; Safety; Sampling; Savings; Signal Transduction; Specificity; Symptoms; Technology; Testing; Tissues; Toxicology; Treatment Cost; Urine; Validation; Withdrawal; accurate diagnosis; bariatric surgery; base; collagenase; cost; design; diagnosis standard; enzyme activity; improved; in vivo; liver biopsy; liver transplantation; man; mass spectrometer; mathematical algorithm; mouse model; nanosensors; nonalcoholic steatohepatitis; pharmacokinetic model; pre-clinical; preclinical toxicity; problem drinker; scaffold; treatment responders; urinary

Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) is dubbed the “stealth epidemic” and in the U.S. alone, 20 percent of the 16 million people who are estimated to have NASH will progress and develop life-threatening conditions including fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. By the year 2020, NASH is projected to be the leading indication for liver transplantation surpassing hepatitis C virus (HCV) and alcoholic related cirrhosis, and by 2025, the total NASH pharmaceutical market size is estimated to reach $15 billion. Currently, the liver biopsy is the “gold standard” for diagnosing and monitoring NASH, yet it is invasive, expensive (~$3,000), and associated with significant patient morbidities. Importantly, a single biopsy provides only an instantaneous `snapshot' of tissue architecture and is unable to identify NASH patients who are `rapid progressors' and thus urgently require treatment, or those on therapy that are `responders'. As a result of these limitations, liver biopsy remains the key bottleneck in the safe, accurate diagnosis and monitoring of NASH. This proposal aims to develop the Glympse liver test (GLT), a noninvasive urine diagnostic that detects the activity of hepatic proteases that drive NASH. GLT consists of an injectable panel of nanosensors that detect proteases involved with inflammation and fibrosis, and produce signals that are detected in urine. The detection signals are amplified by enzymatic action in the liver and then concentrated in the patient's urine for quantification by mass spectrometry. Because enzyme activity is measurable at the molecular level before microscopic changes are evident by biopsy, the test is thus both ultrasensitive and predictive. We will demonstrate the feasibility of formulating GLT nanosensors on an inert polymer scaffold to sense matrix metalloproteinases (MMPs) – a key family of enzymes that are involved in NASH progression and regression. We will then validate the ability of GLT to predict disease progression and regression in a mouse model of NASH, and conduct preclinical toxicology studies in preparation for an IND submission. The GLT will offer clinicians a rapid determination of the state and trajectory of the patient's liver without the morbidity of biopsy, reduce cost of diagnosis from $3,000 to $500, and raise sensitivity by 40%. The benefit to the healthcare system per patient is estimated to be $48,000 in reduced biopsy-associated costs and $145,000 in drug costs over a patient's lifetime, saving more than $12 billion annually for the 20% of NASH patients with progressive disease alone. The impact of the adoption of GLT will reach across multiple constituencies – increasing patient care and comfort, improving physician decision making, accelerating pharmaceutical drug trials, and lowering healthcare costs.

项目摘要/摘要 非酒精性脂肪性肝炎(NASH)被称为“隐形流行病”，仅在美国，20%的 据估计，患有NASH的1600万人将进展并发展为危及生命的疾病 包括纤维化、肝硬变、肝细胞癌和肝功能衰竭。到2020年，纳什预计将 成为超过丙型肝炎病毒(HCV)和酒精相关的肝移植的主要适应症 到2025年，NASH药物市场总规模估计将达到150亿美元。目前， 肝活检是诊断和监测NASH的“黄金标准”，但它具有侵入性，费用昂贵。 (约3,000美元)，并与显著的患者发病率有关。重要的是，一次活检只能提供 组织结构的瞬时快照，并且无法识别哪些NASH患者是快速的 因此迫切需要治疗的人，或那些正在接受治疗的人是“应答者”。由于这些原因， 尽管存在局限性，但肝脏活检仍是安全、准确诊断和监测NASH的关键瓶颈。 这项提议旨在开发GLUPSE肝脏测试(GLT)，这是一种非侵入性的尿液诊断方法，可以检测出 驱动NASH的肝蛋白水解酶活性。GLT由一个可注射的纳米传感器面板组成，可以检测到 蛋白水解酶参与炎症和纤维化，并产生在尿液中检测到的信号。这个 检测信号在肝脏中通过酶作用放大，然后集中在患者的尿液中 用质谱仪进行定量。因为酶的活性以前是可以在分子水平上测量的 显微镜下的变化通过活组织检查是明显的，因此该测试具有极高的敏感性和预测性。我们会 证明在惰性聚合物支架上制备GLT纳米传感器以检测基质的可行性 金属蛋白酶(MMPs)-参与NASH进展和消退的一个关键酶家族。 然后，我们将在小鼠模型中验证GLT预测疾病进展和回归的能力 NASH，并进行临床前毒理学研究，为IND提交做准备。GLT将提供 临床医生能够快速确定患者肝脏的状态和轨迹，而不需要进行活检， 将诊断成本从3,000美元降至500美元，并将灵敏度提高40%。对医疗保健的好处 据估计，每名患者减少的活组织检查相关成本为48,000美元，药品成本为145,000美元 在患者的一生中，每年为20%的进展性NASH患者节省超过120亿美元 仅仅是疾病。采用GLT的影响将覆盖多个受众-越来越多的患者 护理和舒适度，改善医生决策，加快药物试验，并降低 医疗保健成本。