Optimization and Validation of an Indicator Cell Assay for Blood-Based Diagnosis of Alzheimer's Disease

用于阿尔茨海默病血液诊断的指示细胞测定的优化和验证

• 批准号: 9926206
• 负责人: Jennifer Joy Smith
• 金额: $ 99.89万
• 依托单位: PRECYTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926206
• 关键词: Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease therapy; Amyloid beta-42; Biological Assay; Biomedical Research; Biosensor; Blood; Blood Tests; Blood specimen; Cells; Cellular Assay; Characteristics; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Collection; Cultured Cells; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Enrollment; Environment; Failure; Frequencies; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Infectious Diseases Research; Institutes; Laboratories; Malignant neoplasm of lung; Measures; Molecular Profiling; Monitor; Neurons; Pathology; Patients; Pattern; Performance; Pharmacologic Substance; Phase; Population; Process; Quality Control; Risk; Running; Sampling; Serum; Severities; Signal Transduction; Site; Small Business Innovation Research Grant; Source; Specificity; Standardization; Stratification; Subjects Selections; Systems Biology; Testing; Training; Transcript; Validation; assay development; base; blind; cohort; cost; cost effective; effective therapy; high risk; high throughput screening; improved; miniaturize; nonalzheimer dementia; novel; outcome forecast; performance tests; phase 2 study; pre-clinical; predicting response; prospective; response; screening; success; tau-1; tool; transcriptome; treatment response

Project Summary. PreCyte is developing the Indicator Cell Assay Platform (iCAP) as a broadly applicable and inexpensive blood-based assay that can be used for the early detection of disease, disease stage stratification, prognosis and predicting response to therapy for a variety of diseases. The iCAP uses cultured, standardized cells as biosensors, capitalizing on the ability of cells to respond to disease signals present in serum with exquisite sensitivity, as opposed to traditional assays that rely on direct detection of molecules in blood. Developing the iCAP involves exposing cultured cells to serum from normal or diseased subjects, measuring a global differential response pattern, and using it to build a reliable disease classifier based on the expression of a small number of genes. Deploying the iCAP involves measuring only expression of genes that are classifier features using cost-effective tools. We have demonstrated the iCAP for blood-based detection of lung cancer and detection of Alzheimer's disease (AD) at preclinical and early symptomatic stages. In the SBIR Phase II study, conducted in collaboration with the Institute for Systems Biology, Center for Infectious Disease Research, and Seattle institute of Biomedical and Clinical Research, PreCyte has developed an iCAP- AD capable of detecting AD at preclinical and early symptomatic stages in multiple cohorts. For this Phase IIb, we propose to develop and validate a clinical iCAP AD, a high-throughput and inexpensive version of the iCAP for rapidly selecting subjects for clinical trials of AD therapies. From a simple blood test, the clinical AD iCAP will be able to select from a population of subjects 60 years and older, those with either preclinical or early symptomatic AD and specificity against those with non-AD dementia, and may have additional capacity to identify a subset of these candidates who will progress to AD within 2 years. Development and validation of the clinical iCAP-AD will be done in four specific aims: 1) Develop the clinical iCAP-AD, 2) Establish limits for key assay parameters to demonstrate assay robustness, 3) Validate analytical characteristics of the clinical iCAP, and 4) Validate diagnostic characteristics of the clinical iCAP. The goal of this proposal is to mitigate the risks of using a cell-based assay and establish a robust and validated platform for use in selecting subjects for AD clinical trials and patient diagnosis. After implementation in a CLIA environment, this tool will significantly reduce cost and shorten the duration of clinical trials for AD treatments by rapidly selecting early-stage subjects, with potential to identify those who are within 2 years of developing AD. It will also improve success rate of developing an effective treatment for AD as it enables the targeting of patients at preclinical and early symptomatic stages of the disease, which have been demonstrated to be more treatable than later stages, and could also be used for monitoring AD progression and response to treatment.

项目摘要。PreCyte正在开发指示细胞分析平台（iCAP），作为一种广泛适用的 廉价的基于血液的测定可用于疾病的早期检测，疾病阶段分层， 预后和预测对各种疾病的治疗的反应。iCAP使用培养的标准化 细胞作为生物传感器，利用细胞对血清中存在的疾病信号作出反应的能力， 与依赖于直接检测血液中分子的传统检测方法相反， 开发iCAP涉及将培养的细胞暴露于来自正常或患病受试者的血清，测量细胞的增殖。 全局差异响应模式，并使用它来构建基于以下表达的可靠疾病分类器： 少量的基因。部署iCAP仅涉及测量分类器中的基因表达 使用具有成本效益的工具。我们已经证明了iCAP用于基于血液的肺癌检测 以及在临床前和早期症状阶段检测阿尔茨海默病（AD）。 在SBIR II期研究中，与系统生物学研究所、传染病研究中心合作进行， 疾病研究所和西雅图生物医学和临床研究所，PreCyte开发了一种iCAP- AD能够在多个队列中检测临床前和早期症状阶段的AD。对于该IIb期， 我们建议开发和验证临床iCAP AD，这是iCAP的高通量和廉价版本 用于快速选择AD治疗临床试验的受试者。通过简单的血液检测，临床AD iCAP将 能够从60岁及以上的受试者人群中选择临床前或早期 症状性AD和对非AD痴呆患者的特异性，并可能具有额外的能力，以确定 这些候选人中的一部分将在2年内晋升为AD。临床试验的开发和验证 iCAP-AD将在四个特定目标下完成：1）开发临床iCAP-AD，2）建立关键测定的限度 证明试验耐用性的参数，3）临床iCAP的稳定分析特征，以及4） 临床iCAP的诊断特征。本提案的目标是降低使用 一种基于细胞的试验，并建立一个稳健和经验证的平台，用于选择AD临床试验的受试者 患者诊断。在CLIA环境中实施后，该工具将显著降低成本， 通过快速选择早期受试者缩短AD治疗临床试验的持续时间， 确定那些在2年内发展AD的人。它还将提高开发有效的 治疗AD，因为它能够靶向处于疾病临床前和早期症状阶段的患者， 已被证明比晚期更容易治疗，也可用于监测 AD进展和治疗反应。