Photocleavage Technology for Blood-based Multi-Biomarker Alzheimer's Disease Assay
用于基于血液的多生物标志物阿尔茨海默病检测的光裂解技术
基本信息
- 批准号:10227129
- 负责人:
- 金额:$ 125万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:Abeta synthesisAffectAffinityAlzheimer disease detectionAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease diagnosticAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer’s disease biomarkerAmyloid beta-42Amyloid beta-ProteinAntibodiesArea Under CurveAutomationBehaviorBenchmarkingBiological AssayBiological MarkersBloodBostonBusinessesCalibrationCerebrospinal Fluid ProteinsChronicClinicalCognitiveCross ReactionsCustomDementiaDetectionDeteriorationDevelopmentDiagnosticDisease ProgressionEarly DiagnosisEarly InterventionEvaluationGoldHealth Care CostsImmunoassayImmunodiagnosticsIndustryLeadershipLicensingLiquid substanceLongevityMagnetismMalignant neoplasm of prostateManufacturer NameMeasurementMeasuresMethodsMicrospheresModelingNeurodegenerative DisordersPersonsPharmacologic SubstancePhasePhenotypePopulationPopulation GroupPositron-Emission TomographyPublic HealthROC CurveReaderReportingResearchResearch PersonnelRoboticsRoleSamplingSeminalSenile PlaquesSepharoseSerologySerumServicesSpecificitySpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSpinal PunctureSyndromeTechnologyTherapeuticUniversitiesWorkaptamerbaseclinically relevantcognitive functioncommercializationcostdesigndetection limitdisorder controlhuman old age (65+)improvedmalignant breast neoplasmmultiplex assaymultiplex detectionnovelnovel strategiesparticleprotein biomarkersscreeningtau Proteins
项目摘要
Summary/Abstract
Alzheimer's Disease (AD) is a chronic neurodegenerative disease characterized by progressively worsening
dementia, a syndrome associated with deterioration in cognitive function, behavior and ability to perform everyday
activities. AD currently affects over 5.7 million persons in the U.S. with over 70% over the age of 65 and
approximately 30 million world-wide. The public health costs due to AD is expected to grow exponentially due to
the large expansion of the population over 65 which is estimated to reach over 100 million by 2060. Importantly,
early diagnosis of AD is critical for application of therapeutics early in the disease progression, offering the promise
of reducing debilitating effects and extending life span.
Although the major clinical methods of diagnosing AD rely either on detection of biomarkers such as β-amyloid and
tau proteins from cerebrospinal fluid (CSF) or PET imaging, these assays are limited by their invasiveness (e.g. lumbar
puncture) or high costs, respectively, and not suitable as a front-line AD diagnostic. In contrast, a blood-based assay
would be highly suitable for screening large population groups (e.g. persons over 60) for early AD. While blood-based
assays of single biomarkers show significant promise for early detection of AD (e.g. for β-amyloid), it is likely that a
panel of several biomarkers measured using a multiplex assay will ultimately emerge as necessary to achieve
sufficient specificity to have clinical utility, especially in distinguishing different neurodegenerative diseases that
have similar phenotypes. An additional major problem in the development of sensitive and accurate blood-based
AD assays is the matrix effect. This effect is caused by the presence of the much more abundant molecules in blood
which interfere with detection of the low-abundance biomarkers.
We evaluated and successfully demonstrated during Phase I a new approach to multiplex serological AD assays
termed PC-PURE™ which is designed to both enrich low-abundance biomarkers and eliminate the matrix effect.
This technology is based on the use of novel photocleavable (PC) linkers developed by AmberGen which are
incorporated into affinity capture agents such as aptamers or antibodies. We successfully demonstrated the
feasibility of PC-PURE™ AD immunoassays by enrichment and multiplex detection of 3 model AD biomarkers
(Aβ40, Aβ42 and tau). Our results show that PC-PURE™ when applied as a “front-end” to a commercially available
multiplexed Luminex® xMAP® assay improves sensitivity by 30 to 667-fold compared to the same assay without
PC-PURE™. Furthermore, PC-PURE™ provides a much more accurate estimate of absolute biomarker
concentration since both the calibration curves and biomarkers extracted from the biospecimen are measured in a
similar medium. During Phase II, PC-PURE™ will be further optimized for measurement of a model panel of 16
AD biomarkers using 300 AD confirmed and control serum samples and compared to results obtained using a bead-
based immuno-MALDI-MS method that is currently one of the most accurate means of measuring AD biomarkers
in serum. Commercial products will include PC-PURE™ multiplex immunoassay kits targeting AD biomarkers.
摘要/摘要
阿尔茨海默病(AD)是一种慢性神经退行性疾病,其特征是病情逐渐恶化
痴呆症,一种与认知功能、行为和日常执行能力恶化相关的综合征
活动。目前,美国有超过 570 万人患有 AD,其中 70% 以上年龄在 65 岁以上
全球约有 3000 万。 AD 造成的公共卫生成本预计将呈指数级增长
65 岁以上人口大幅增长,预计到 2060 年将超过 1 亿。重要的是,
AD 的早期诊断对于疾病进展早期的治疗应用至关重要,这提供了希望
减少衰弱影响并延长寿命。
尽管诊断 AD 的主要临床方法依赖于生物标志物的检测,例如 β-淀粉样蛋白和
来自脑脊液 (CSF) 或 PET 成像的 tau 蛋白,这些检测方法因其侵入性而受到限制(例如腰椎
穿刺)或成本较高,并且不适合作为一线 AD 诊断。相比之下,基于血液的检测
非常适合筛查大量人群(例如 60 岁以上的人)的早期 AD。虽然以血液为基础
单一生物标志物的检测显示出早期检测 AD 的重大前景(例如 β-淀粉样蛋白),很可能
使用多重测定测量的几种生物标志物组最终将根据需要出现以实现
足够的特异性具有临床实用性,特别是在区分不同的神经退行性疾病方面
具有相似的表型。开发灵敏、准确的血液检测的另一个主要问题
AD测定是基质效应。这种效应是由血液中存在更丰富的分子引起的
干扰低丰度生物标志物的检测。
我们在第一阶段评估并成功证明了一种多重血清学 AD 检测的新方法
称为 PC-PURE™,旨在富集低丰度生物标志物并消除基质效应。
该技术基于 AmberGen 开发的新型光可裂解 (PC) 连接器的使用,该连接器是
掺入亲和捕获剂,例如适体或抗体。我们成功地展示了
通过富集和多重检测 3 种模型 AD 生物标志物进行 PC-PURE™ AD 免疫测定的可行性
(Aβ40、Aβ42 和 tau)。我们的结果表明,当 PC-PURE™ 用作市售产品的“前端”时
与未使用多重 Luminex® xMAP® 检测的相同检测相比,其灵敏度提高了 30 至 667 倍
PC-PURE™。此外,PC-PURE™ 可以更准确地估计绝对生物标志物
浓度,因为从生物样本中提取的校准曲线和生物标志物都是在
类似的介质。在第二阶段,PC-PURE™ 将进一步优化,以测量 16 个模型面板
使用 300 个 AD 确认和对照血清样本进行 AD 生物标记,并与使用珠子获得的结果进行比较
基于免疫-MALDI-MS 方法,是目前测量 AD 生物标志物最准确的方法之一
在血清中。商业产品将包括针对 AD 生物标志物的 PC-PURE™ 多重免疫测定试剂盒。
项目成果
期刊论文数量(0)
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Mark Lim其他文献
Mark Lim的其他文献
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