Diagnostic aptamer reagents to develop multi-analyte blood test for pre-clinical, mild and moderate Alzheimer's disease

诊断适体试剂用于开发针对临床前、轻度和中度阿尔茨海默病的多分析物血液检测

• 批准号: 10597840
• 负责人: BHARAT GAWANDE
• 金额: $ 44.56万
• 依托单位: APTUS BIOSCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597840
• 关键词: Address; Affinity; Age; Algorithmic Analysis; Algorithms; Alzheimer' s Disease; Alzheimer' s disease blood test; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amino Acids; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Area; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biological Sciences; Blood; Blood Tests; Caring; Cerebrospinal Fluid; Clinical Laboratory Information Systems; Cognitive; Cytidine; DNA Library; Dementia; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Early identification; Early treatment; Economic Burden; Engineering; Epitopes; Evolution; Feasibility Studies; Friends; Generations; Grant; Healthcare Systems; Hydrophobicity; Image; In Vitro; Individual; Intervention; Length; Ligand Binding; Literature; Measures; Medical; Medical Care Costs; Methods; Molecular Biology; Neurofibrillary Tangles; Nucleotides; Organic Synthesis; Paper; Peptides; Performance; Persons; Phase; Phosphorylated Peptide; Phosphorylation; Plasma; Population; Positron-Emission Tomography; Preclinical Testing; Probability; Production; Protein Isoforms; Proteins; Proteomics; Publishing; ROC Curve; Reagent; Reporting; Reproducibility; Research; Sampling; Scientist; Sensitivity and Specificity; Side; Signal Transduction; Small Business Innovation Research Grant; Specificity; Surface; Symptoms; Technology; Testing; Training; Universities; Uridine; Validation; Washington; Work; aptamer; base; biomarker performance; blood-based biomarker; candidate selection; cloud based; cohort; commercialization; cost; cross reactivity; diagnostic value; economic cost; experience; experimental study; genetic information; high risk; human old age (65+); improved; in-vitro diagnostics; medical schools; novel coronavirus; nuclear imaging; nucleobase; phase 2 study; professor; scale up; specific biomarkers; synthetic peptide; tau Proteins; tau-1

Diagnostic aptamer reagents to develop multi-analyte blood test for pre-clinical, mild and moderate Alzheimer’s disease Aptus Biosciences, LLC Bharat Gawande Summary Today, 6.2 million Americans are living with Alzheimer’s disease (AD), resulting in $355 billion in annual medical care costs. As the US population over age 65 grows, the number of Americans living with AD is expected to increase to 12.7 million by 2050. AD is a slow progressing disease, and it may take up to 20 years before symptoms are recognizable. While new treatments are emerging, that may help to control or modify the disease, early detection using a simple blood test is critical to individuals with AD. Importantly, recent studies have shown promising results with blood-based biomarkers that are specific for AD. However, there is clearly a lack of high affinity reagents that can bind to these biomarkers and be used to develop sensitive and easily accessible blood tests. Aptus Biosciences will use modified aptamer selection technology, to create highly sensitive and specific reagents that detect blood biomarkers of AD which cause neurofibrillary tangles (NFTs), a hallmark of AD. We will deliver aptamer reagents developed from an improvised In Vitro selection method using hydrophobic modified nucleotides that can bind to tau protein, and multiple isoforms of phosphorylated tau (p-tau) protein with pico-molar affinity. Each targeted selection will generate aptamers that bind to various epitopes on specific p-tau targets with picomolar affinity and that will be used to develop a simple bead-based aptamer sandwich assay in which one aptamer will capture p-tau biomarker and other aptamer will result in a signal generation to measure the plasma concentrations of these analytes. Our modified aptamer reagents are potentially better than unmodified aptamers and large antibody-based reagents, which are not as sensitive or specific because of their large size, low affinity, and cross-reactivity in multi-analyte assays. Specifically, we will use selections to create modified aptamers that bind to specific validated phosphorylated isoforms of tau. In addition, we will develop a simple bead-based multi-analyte aptamer sandwich assay to measure p-tau isoforms in plasma samples obtained from cerebrospinal fluid (CSF) Aβ42 positive, AD-confirmed individuals and compare them with plasma samples obtained from cognitively normal, Aβ42 negative individuals without AD. If this Phase I grant is successful, in Phase II, we will optimize aptamer reagents to improve the sensitivity and specificity of the assay, scale-up aptamer reagent production, develop a cloud-based algorithm using a training sample set, and validate the assay using test samples to correctly identify early AD in a large cohort. The multi- analyte aptamer-based assay will make it far superior to existing qualitative, invasive, and expensive diagnostic tests. If successful, this simple blood test will enhance the lives of millions of Americans who are at high risk of developing AD due to the ability of the test for early detection, thus resulting in early treatment interventions and decreasing the huge economic burden to the healthcare system.

诊断适体试剂，用于开发临床前、轻度和 中度阿尔茨海默病 Aptus Biosciences，LLC 巴拉特·加万德 总结 今天，620万美国人患有阿尔茨海默病（AD），每年造成3550亿美元的损失。 医疗费用。随着美国65岁以上人口的增长，预计美国AD患者的数量将增加。 到2050年增加到1270万。AD是一种进展缓慢的疾病，可能需要长达20年的时间才能恢复。 症状是可识别的。虽然新的治疗方法正在出现，这可能有助于控制或改变这种疾病， 使用简单的血液测试进行早期检测对AD患者至关重要。重要的是，最近的研究表明， 有希望的结果与血液为基础的生物标志物是具体的AD。然而，显然缺乏高 可以与这些生物标志物结合并用于开发敏感且易于获得的血液的亲和试剂 试验. Aptus Biosciences将使用改良的适体选择技术， 检测AD的血液生物标志物的试剂，所述AD的血液生物标志物引起神经元缠结（NFT），这是AD的标志。我们 将提供从使用疏水性的简易体外选择方法开发的适体试剂， 可结合tau蛋白的修饰核苷酸，以及磷酸化tau蛋白的多种同种型（p-tau 具有皮摩尔亲和力。每次靶向选择将产生与特异性抗体上的各种表位结合的适体。 具有皮摩尔亲和力的p-tau靶点，并将用于开发简单的基于珠的适体夹心 其中一种适体将捕获p-tau生物标志物，而另一种适体将导致信号产生， 测量这些分析物的血浆浓度。我们的改良适体试剂可能比 未修饰的适体和大的基于抗体的试剂，其由于其 大尺寸、低亲和力和多分析物测定中的交叉反应性。具体来说，我们将使用选择来创建 修饰的适体，其结合特异性验证的磷酸化tau同种型。此外，我们会制定一个 用于测量获得的血浆样品中的p-tau同种型的简单的基于珠的多分析物适体夹心测定 从脑脊液（CSF）Aβ42阳性、AD确诊的个体中提取，并将其与血浆样本进行比较 从认知正常、Aβ42阴性、无AD的个体中获得。 如果第一阶段资助成功，在第二阶段，我们将优化适体试剂，以提高灵敏度， 分析的特异性，扩大适体试剂生产，使用训练 样本集，并使用测试样本验证测定法，以正确鉴定大型队列中的早期AD。该多 基于分析物适体的测定将使其远远上级现有的定性、侵入性和昂贵的诊断方法， 试验.如果成功的话，这种简单的血液测试将提高数百万美国人的生活， 由于检测能够早期发现，从而导致早期治疗干预， 减轻医疗系统的巨大经济负担。