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.

有了有效的治疗方法，对阿尔茨海默氏病（AD）和阿尔茨海默氏病相关痴呆症（ADRD）的疾病进展的早期发现和监测对于AD/ADRD的管理和干预至关重要。 FDA获得了新的单克隆抗体药物靶向淀粉样蛋白β的靶向淀粉样蛋白β的加速批准，FDA在处理正确分层的患者时可能更有效，强调了对AD的早期和生物标志物特异性诊断的紧迫临床需求。当前具有AD生物标志物的靶向极性发射断层扫描（PET）成像和脑脊液（CSF）样品蛋白质组学分析的临床实践并不可取，因为由于成像设施或CSF收集的Imavasive Lumbar Puncture的可用性和可及性，因此可以早期检测的可取疗法（POC）解决方案。鉴于非侵入性，成本效益和在一般临床环境中易于获取的优势，基于血液的AD生物标志物检测是用于AD/ADRD早期诊断的POC诊断工具。虽然两个平台，即Aβ40/Aβ42检测的PROCITIODADTM，而SIMOA®用于磷酸-TAU 181（P-TAU181），最近被授予FDA的临床用途FDA突破性设备名称，但两种系统都需要高度专业的高端测试工具来进行样品测试，限制较低的可用性，尤其是在较低的社区中，尤其是有限的范围和较低的社区，或有限的范围，或者是有限的。此外，PROCITIODADTM和SIMOA®使用抗体涂层的磁珠来捕获靶向的AD生物标志物。然而，珠子表面的血清蛋白的非特异性添加吸收形成了一种蛋白电晕，可以阻止抗体捕获生物标志物。在此SBIR I期项目中，我们旨在开发一个多路复用的AD生物标志物检测平台，该平台可以整合两种创新技术，即超磁氧化铁纳米棒（IONR）和抗生物烯烃聚合物涂层，用于IONRS，用于用于在血液样品中多发性地进行六个Ad BioMarker的IONRS。 IONR提供的磁性与​​PROCITIODADTM和SIMOA®中使用的磁珠一样强，并且还充当纳米 - 刺激杆，可在替代电磁场下改善样品混合，以更有效的生物标志物捕获。抗生物性涂层可最大程度地减少在离子上的非特异性血清蛋白吸附，以保留血液样品中靶向生物标志物的抗体亲和力。 The Phase I project will focus on (1) developing a prototype device enabling efficient blood sample mixing with anti-biofoling 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）测试开发的系统并使用患者样品评估其性能，然后将结果与同一患者的临床诊断和成像发现进行比较和纠正。如果成功，该设备将通过II期中的大规模测试进一步评估，将为处于危险中的个体中的筛查和检测AD以及监视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。