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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease blood test Alzheimer&apos s disease diagnosis Alzheimer&apos 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

项目摘要

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.

诊断适体试剂可开发用于临床前、轻度和慢性疾病的多分析物血液检测中度阿尔茨海默病 Aptus 生物科学有限公司巴拉特·高万德概括如今，620 万美国人患有阿尔茨海默病 (AD)，每年造成 3550 亿美元的损失随着美国 65 岁以上人口的增长，预计患有 AD 的美国人数量将会增加。到 2050 年将增加到 1270 万。 AD 是一种进展缓慢的疾病，可能需要长达 20 年的时间虽然新的治疗方法正在出现，但症状是可以识别的，这可能有助于控制或改变疾病。重要的是，最近的研究表明，使用简单的血液测试进行早期检测对于 AD 患者至关重要。 AD 特异性血液生物标志物取得了有希望的结果，但显然缺乏高水平的标志物。可以与这些生物标志物结合并用于开发敏感且易于获取的血液的亲和试剂测试。 Aptus Biosciences 将使用改良的适体选择技术，创造高度敏感和特异的核酸适体选择技术。检测 AD 血液生物标志物的试剂，这些生物标志物会导致神经原纤维缠结 (NFT)，这是 AD 的一个标志。将提供使用疏水性的临时体外选择方法开发的适体试剂可与 tau 蛋白结合的修饰核苷酸以及磷酸化 tau (p-tau) 蛋白的多种亚型具有皮摩尔亲和力的每个目标选择都会产生与特定的各种表位结合的适体。 p-tau 靶标具有皮摩尔亲和力，将用于开发简单的基于珠子的适配体三明治其中一个适体将捕获 p-tau 生物标志物，而其他适体将产生信号以我们的改良适体试剂可能比测量这些分析物的血浆浓度更好。未修饰的适体和基于大型抗体的试剂，由于其敏感性或特异性不那么高具体来说，我们将使用选择来创建多分析物测定中的大尺寸、低亲和力和交叉反应性。与经过验证的特定 tau 磷酸化亚型结合的修饰适体此外，我们将开发一种简单的基于微珠的多分析物适体夹心法，用于测量获得的血浆样品中的 p-tau 异构体分析形式来自脑脊液 (CSF) Aβ42 阳性、AD 确诊个体的样本，并将其与血浆样本进行比较从认知正常、Aβ42 阴性、无 AD 的个体获得。如果第一期资助成功，在第二期，我们将优化适体试剂以提高灵敏度和测定的特异性、扩大适体试剂的生产、使用训练开发基于云的算法样本集，并使用测试样本验证检测方法，以正确识别大型队列中的早期 AD。基于分析物适体的检测将使其远远优于现有的定性、侵入性且昂贵的诊断如果测试成功，这种简单的血液测试将改善数百万高风险美国人的生活。由于测试能够早期发现而发展 AD，从而导致早期治疗干预并减轻医疗保健系统的巨大经济负担。