Blood-based diagnostics for Alzheimer's Disease

阿尔茨海默病的血液诊断

• 批准号: 9231053
• 负责人: CLAUDIO SOTO
• 金额: $ 6.47万
• 依托单位: AMPRION, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231053
• 关键词: Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Biochemical; Biological; Biological Assay; Blinded; Blood; Blood Tests; Brain; Brain Injuries; Businesses; Cause of Death; Cerebrospinal Fluid; Cerebrum; Chemical Structure; Clinical; Correlation Studies; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Elderly; Evaluation; Event; Goals; Health; Human; In Vitro; Individual; Institution; Knowledge; Laboratory Diagnosis; Lead; Liquid substance; Medical; Mole the mammal; Monitor; Mutation; Nerve Degeneration; Patients; Persons; Phase; Plasma; Population; Predictive Value; Prion Diseases; Prions; Property; Proteins; Reproducibility; Sampling; Secure; Sensitivity and Specificity; Small Business Technology Transfer Research; Specificity; Staging; Structure; Techniques; Technology; Testing; Time; Tissues; Transgenic Animals; Transgenic Mice; Urine; Validation; Work; abeta accumulation; abeta oligomer; authority; base; clinical Diagnosis; design; disease diagnosis; experience; familial Alzheimer disease; high risk; mild cognitive impairment; mouse model; nervous system disorder; polymerization; pre-clinical; programs; protein misfolding; protein misfolding cyclic amplification; research study

DESCRIPTION (provided by applicant): This proposal is for a phase I/II fast track project for the STTR program with the main goal to develop a blood test for Alzheimer's disease (AD) diagnosis. AD is the most common dementia in the elderly population and one of the leading causes of death in the developed world. One of the main problems in AD is the lack of an early, sensitive and objective laboratory diagnosis to identify individuals that will develop the disease before substantial brain damage. Compelling evidences point that the hallmark event in AD is the misfolding, aggregation and brain accumulation of amyloid-beta (Aβ) protein. Aβ aggregation follows a seeding-nucleation mechanism and involves several intermediates, including soluble oligomers and protofibrils. Recent evidence has shown that Aβ oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration in AD. Our working hypothesis is that detection of misfolded Aβ oligomers circulating in blood may be the basis for an early biochemical diagnosis for AD. Our approach is to use the functional property of misfolded oligomers of being capable to catalyze the polymerization of the monomeric protein as a way to detect them. We have recently invented the protein misfolding cyclic amplification (PMCA), which represent a platform technology to detect very small quantities of seeding-competent misfolded oligomeric proteins associated with various protein misfolding diseases. Currently, PMCA has been adapted to detect misfolded prion protein implicated in prion diseases in various biological fluids, including blood and urine and more recently soluble Aβ oligomers in cerebrospinal fluid of AD patients. The major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded Aβ oligomers in human blood, perform studies of specificity and sensitivity using large number of samples and evaluate the utility of Aβ-PMCA for pre-clinical identification of people in the way to develop AD. The results generated in this project may lead to the first biochemical test for blood-based diagnosis of AD. The studies included in this project will constitute the basis for regulatory approval of the test that Amprion will commercialize.

描述（由适用提供）：该提案是针对STTR计划的I/II期快速轨道项目的主要目标，其主要目标是为阿尔茨海默氏病（AD）诊断进行血液检查。广告是最古老的人口中最常见的痴呆症，也是发达国家的主要死亡原因之一。 AD的主要问题之一是缺乏早期，敏感和客观的实验室诊断，无法在脑损伤实质性损害之前识别会发展该疾病的个体。令人信服的证据指出，AD中的标志性事件是淀粉样蛋白（Aβ）蛋白的错误折叠，聚集和脑积累。 Aβ聚集遵循播种核酸的机制，涉及几种中间体，包括固体寡聚物和原纤维。最近的证据表明，Aβ低聚物在生物流体中正在循环，这些结构似乎是AD中诱导脑变性的关键。我们的工作假设是，在血液中循环的错误折叠的Aβ低聚物的检测可能是AD早期生化诊断的基础。我们的方法是使用能够催化单体蛋白聚合的错误折叠的低聚物的功能性能。我们最近发明了蛋白质错误折叠环状扩增（PMCA），该蛋白质代表了一种平台技术，可检测与各种蛋白质错误折叠疾病相关的非常折叠式的失误寡聚的寡聚蛋白。目前，PMCA已适应各种生物液中的主要疾病中隐含的不折叠的prion蛋白，包括血液和尿液以及最近在AD患者的脑脑脊液中固体Aβ低聚物。该项目的主要目的是适应PMCA技术，以使用大量样品对人体血液中错误折叠的Aβ低聚物的特异性和高度敏感的检测进行研究，并评估Aβ-PMCA的效用，以在开发AD的方式中对临床前识别人的效用。该项目中产生的结果可能会导致对AD基于血液的诊断的首次生化测试。该项目中包括的研究将构成对Amprion将商业化测试的监管批准的基础。