Highly Sensitive and Robust Blood Test Platform for Screening and Early Detection of Alzheimer's Disease

用于筛查和早期检测阿尔茨海默病的高灵敏度和稳健的血液检测平台

• 批准号: 10515572
• 负责人: Yuancheng Li
• 金额: $ 39.98万
• 依托单位: 5M BIOMED, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515572
• 关键词: Adsorption; Aducanumab; Aftercare; Alzheimer disease detection; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease test; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Antibody Affinity; Archives; Area; Attenuated; Binding; Biological Markers; Blocking Antibodies; Blood; Blood Tests; Blood specimen; Brain imaging; Cerebrospinal Fluid; Clinical; Collaborations; Collection; Communities; Complex; Data; Detection; Development; Devices; Diagnosis; Disease Progression; Disease Surveillance; Drug Targeting; Early Diagnosis; Electromagnetic Fields; Electromagnetics; Equipment; Evaluation; Exhibits; Fluorescence; Formulation; Goals; Grant; Human; Immunomagnetic Separation; Immunoprecipitation; Individual; Intervention; Label; Legal patent; Ligands; Magnetism; Mass Spectrum Analysis; Measures; Microtubules; Monitor; Noise; Pathogenesis; Patients; Performance; Phase; Plasma; Polymers; Positron-Emission Tomography; Procedures; Production; Proteins; Proteomics; Reproducibility; Research; Resource-limited setting; Resources; Risk; Sampling; Sensitivity and Specificity; Serum Proteins; Small Business Innovation Research Grant; Spinal Puncture; Surface; System; Technology; Testing; Therapeutic Monoclonal Antibodies; Whole Blood; abeta deposition; antibody conjugate; base; clinical diagnosis; clinical imaging; clinical practice; clinical translation; commercialization; cost; cost effective; cost effectiveness; detection method; detection platform; diagnostic tool; early detection biomarkers; effective therapy; effectiveness evaluation; health disparity; imaging facilities; improved; in-vitro diagnostics; innovation; innovative technologies; instrument; iron oxide; magnetic beads; mild cognitive impairment; multiplex detection; nano; nanoparticle; nanorod; nanosized; neurofilament protein L; patient response; patient stratification; point of care; point of care testing; point-of-care detection; point-of-care diagnostics; preservation; prototype; scale up; screening; single molecule; specific biomarkers; success; targeted biomarker; tau Proteins; tau-1; treatment response

With an effective treatment yet to be developed, early detection and surveillance of disease progression for Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) are critical for the management and intervention of AD/ADRD. The recent accelerated approval of the new monoclonal antibody drug targeting amyloid-β, Aducanumab®, by FDA, which is likely more efficacious when treating properly stratified patients, highlighted the urgent clinical need for early and biomarker-specific diagnosis of AD. Current clinical practices with AD biomarker targeted positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) sample based proteomics analysis are not desirable point-of-care (POC) solutions for early detection due to the limited availability and accessibility of imaging facilities or invasive lumbar puncture for CSF collection. Given the advantages of non-invasiveness, cost effectiveness and easy access in general clinical settings, blood-based AD biomarker detections are more applicable POC diagnostic tools for early diagnosis of AD/ADRD. While two platforms, i.e., PrecivityADTM for Aβ40/Aβ42 detection and Simoa® for phospho-tau 181 (p-tau181), were recently granted FDA Breakthrough Device designations for clinical uses, both systems require highly specialized high-end instruments for sample testing, limiting their wide availability, particularly in the communities and regions with low or limited resources and health disparity. Furthermore, PrecivityADTM and Simoa® use antibody-coated magnetic beads to capture targeted AD biomarkers. However, the non-specific adsorption of serum proteins on the surface of beads forms a protein corona that can block the antibody from capturing biomarkers. In this SBIR Phase I project, we aim to develop a multiplexed AD biomarker detection platform that can integrate two innovative technologies, i.e., ultramagnetic iron oxide nanorods (IONRs) and anti-biofouling polymer coating for IONRs, for multiplexing six AD biomarkers in blood samples. The IONRs provide as strong magnetism as the magnetic beads used in PrecivityADTM and Simoa®, and also function as nano-stirring-bars to improve sample mixing, under an alternating electromagnetic field, for more efficient biomarker capturing. The anti-biofouling coating minimizes non-specific serum protein adsorption on IONRs to preserve the antibody affinity for targeted biomarkers in blood samples. The Phase I project will focus on (1) developing a prototype device enabling efficient blood sample mixing with anti-biofouling IONRs and multiplexed detection of six AD biomarkers, i.e., Aβ40, Aβ42, total-tau (t-tau), p-tau181, amyloid precursor protein (APP669-711), and neurofilament light protein (NfL), and (2) testing the developed system and evaluate its performance using the patient samples, followed by comparing and correlating the results with clinical diagnosis and imaging findings of the same patients. If successful, the device, to be further assessed by large-scale tests in Phase II, will provide a robust and cost-effective POC detection for screening and detecting AD in individuals at risk as well as surveilling the progression and treatment response for patients.

由于有效的治疗方法尚未开发出来，早期发现和监测阿尔茨海默病(AD)和阿尔茨海默病相关痴呆(ADRD)的疾病进展对于AD/ADRD的管理和干预至关重要。美国食品和药物管理局最近加速批准了针对淀粉样蛋白β的新型单抗药物Aducanumab®，该药物在治疗适当分层的患者时可能更有效，这突显了临床上对AD早期和生物标志物特异性诊断的迫切需求。目前使用AD生物标记物靶向正电子发射断层扫描(PET)成像和基于脑脊液(CSF)样本的蛋白质组学分析的临床实践并不是用于早期发现的理想的护理点(POC)解决方案，因为成像设备的可用性和可及性有限，或者用于脑脊液采集的侵入性腰椎穿刺术。基于血液的AD生物标志物检测具有非侵入性、成本效益和在一般临床环境下易于获得的优势，是更适用于AD/ADRD早期诊断的POC诊断工具。虽然两个平台，即用于Aβ40/Aβ42检测的PreciityADTM和用于磷酸化tau181的SIMOA®(p-tau181)最近获得了FDA的临床突破性设备称号，但这两个系统都需要高度专业的高端仪器来进行样本检测，这限制了它们的广泛使用，特别是在资源低或有限且健康差距较大的社区和地区。此外，PreciityADTM和SIMOA®使用抗体包被的磁珠捕获目标AD生物标记物。然而，血清蛋白在珠子表面的非特异性吸附形成了一个蛋白质日冕，可以阻止抗体捕获生物标志物。在SBIR第一期项目中，我们的目标是开发一个多路AD生物标记物检测平台，该平台可以集成两项创新技术，即超磁性氧化铁纳米棒(IONRs)和用于IONRs的防生物污垢聚合物涂层，用于对血液样本中的6个AD生物标记物进行多路复用。IONRs提供与PreciityADTM和SIMOA®中使用的磁珠一样的强大磁性，还可以用作纳米搅拌棒，在交变电磁场下改善样品混合，从而更有效地捕获生物标记物。抗生物污损涂层将非特异性血清蛋白在IONRs上的吸附降至最低，以保持与血液样本中目标生物标记物的抗体亲和力。第一阶段的项目将专注于(1)开发一种原型设备，实现高效的血液样本与抗生物污损IONRs的混合，并对6种AD生物标志物，即Aβ40、Aβ42、Total-tau(t-tau)、p-tau181、淀粉样前体蛋白(APP669-711)和神经细丝光蛋白(NFL)进行多路检测，以及(2)使用患者样本测试所开发的系统并评估其性能，然后将结果与相同患者的临床诊断和成像结果进行比较和关联。如果成功，该设备将通过第二阶段的大规模测试进行进一步评估，将为筛查和检测有AD风险的个人以及监测患者的进展和治疗反应提供强大且具有成本效益的POC检测。