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.

诊断性的纠纷试剂以开发用于临床前，轻度和 中度阿尔茨海默氏病 Aptus Biosciences，LLC 巴拉特·加瓦德（Bharat Gawande） 概括 如今，有620万美国人患有阿尔茨海默氏病（AD），每年有3550亿美元 医疗费用。随着65岁以上的美国人口的增长，预计拥有广告的美国人的数量 到2050年增加到1270万。广告是一种缓慢的疾病，最多可能需要20年 症状是可以识别的。尽管新疗法正在出现，但这可能有助于控制或改变疾病，但 使用简单的血液检查的早期检测对于AD患者至关重要。重要的是，最近的研究表明 具有特定于AD的血液的生物标志物的有希望的结果。但是，显然缺乏 亲和力试剂可以与这些生物标志物结合并用于发展敏感且易于获得的血液 测试。 Aptus Biosciences将使用修改的APATMER选择技术，以创建高度敏感和特定的 检测AD的血液生物标志物的试剂引起了神经原纤维缠结（NFTS），这是AD的标志。我们 将使用疏水性提供从改进的体外选择方法开发的APATMER试剂 可以与tau蛋白结合的修饰核苷酸，以及磷酸化tau（p-tau）蛋白的多种同工型 具有pico摩尔亲和力。每个目标选择都将生成适体，以与特定的各种表位结合 具有皮摩尔亲和力的P-TAU靶标，将用于开发简单的基于珠的Apatmer三明治 一个纠正者将捕获p-tau生物标志物和其他置式的测定法会导致信号产生 测量这些分析物的血浆浓度。我们修改的APATMER试剂可能比 未修饰的适体和大型基于抗体的试剂，由于它们 多分析物测定中的大尺寸，低亲和力和交叉反应性。具体来说，我们将使用选择来创建 修饰的适体与特异性验证的Tau的磷酸化同工型结合。此外，我们将开发一个 简单的基于珠的多分析型APATMER三明治测定法，以测量获得的血浆样品中的P-TAU同工型 从脑脊液（CSF）Aβ42阳性，被广告确认的个体，并将其与等离子体样品进行比较 从没有AD的认知正常的Aβ42负个体获得。 如果此阶段I赠款成功，那么在第二阶段，我们将优化适应试剂以提高灵敏度和 评估的特异性，扩展ATAMER试剂生产，使用训练开发基于云的算法 样品集，并使用测试样品验证测定，以在大型队列中正确识别早期AD。多 基于分析物的基于分析物的测定将使其优于现有的定性，侵入性和昂贵的诊断 测试。如果成功，这种简单的血液检查将改善数百万美国人的生活 由于测试的早期检测能力而开发AD，因此导致了早期治疗干预措施 并减少了医疗体系的巨大经济燃烧。