DEVELOPMENT OF NOVEL BIOMARKERS FOR ALZHEIMER'S DISEASE

描述（由申请人提供）：对于用于阿尔茨海默病（AD）早期发作和疾病进展分期的鉴别诊断的新型生物标志物存在关键的未满足的需求。目前，AD的确诊需要脑组织活检或尸检，这只能在患者死亡后进行。目前，在患者样本（如脑脊液（CSF）、血液和尿液）中尚未鉴定出可用于明确监测AD进展或消退的有效生物标志物。大多数方法集中于患者样品中单个蛋白质如tau和A2作为生物标志物的定量变化。这些研究已达成共识，即CSF中总tau和p-tau的增加以及伴随的A21-42的减少可能指示神经变性。然而，这些变化不是AD的特异性指标，也可能发生在其他形式的痴呆症中。因此，这些生物标志物不能用于AD早期发作的鉴别诊断和疾病进展的分期。基于蛋白质-蛋白质相互作用的范例而不是特定蛋白质水平的新型生物标志物的开发可能为更早和更特异的诊断和疾病监测创造机会，以更好地管理患者。使用测量蛋白质之间的病理相互作用的方法可能提供迫切需要的新的AD生物标志物。这些生物标志物还可以作为药物靶标，用于鉴定治疗AD的新药物疗法，并在用于治疗AD时监测不同的治疗效果。OLIGOMERIX正在评估基于含有tau寡聚体的可溶性复合物和含有tau和A21-42的复合物的新型AD生物标志物。用有限数量的CSF样品进行的初步可行性研究已经表明，与非AD对照相比，来自AD的CSF中的tau寡聚体和tau- A21-42复合物增强。开发了不同形式的ELISA来测量CSF中的这些参数。本项目的目的是使用统计学显著数量的临床腰椎CSF样本（包括重度、轻度和年龄匹配的非AD对照）扩展初步研究，以评估tau寡聚体tau A2和tau-apoE复合物作为AD早期检测和进展的特异性生物标志物的潜力。这项工作将与哥伦比亚大学医学中心陶布阿尔茨海默病和大脑老化研究所的理查德·梅耶和劳伦斯·霍尼格博士合作进行。拟议计划的具体目标如下：“开发AD生物标志物测定法，测量CSF中tau寡聚体和tau与A2或apoE的复合物“使用临床CSF样本对开发的生物标志物测定法进行可行性研究为此，Honig博士将提供约250份CSF样本，用于生物标志物的统计学显著性研究。OLIGOMERIX将对去识别设盲样本进行ELISA，Dr. Honig将分析数据。生物标志物可以被授权给制药行业，用于靶向tau寡聚体、tau-A2或tau-apoE复合物的化合物的临床评价。关键词阿尔茨海默病，生物标志物，tau蛋白，A2，载脂蛋白E，寡聚体。公共卫生相关性：该计划的重点是基于蛋白质-蛋白质相互作用的范式，识别和开发阿尔茨海默病（AD）的新生物标志物。目前，AD生物标志物研究主要集中在AD病因学中涉及的蛋白质水平的定量变化。除了AD，这些变化也可能发生在其他一些形式的痴呆中，因此，不是AD的特异性指标。在这里，我们提出了评估新的AD生物标志物的基础上可溶性复合物含有关键蛋白球员在AD：tau，A21-42和apoE。我们的目标是1）开发生物标志物测定以测量人CSF样品中tau蛋白与其自身（tau寡聚体）、A2或apoE的相互作用，2）使用显著大量的CSF样品评估使用tau寡聚体或tau与A2或apoE的复合物作为AD的生物标志物的可行性。

DESCRIPTION (provided by applicant): There is a critical unmet need for novel biomarkers for differential diagnosis of Alzheimer's disease (AD) at early onset and to stage disease progression. Presently, definitive diagnosis of AD requires tissue biopsy or autopsy of the brain, which can occur only after the patient dies. Currently, there are no validated biomarkers identified in patient samples such as cerebrospinal fluid (CSF), blood, and urine that can be used to definitely monitor the progression or regression of AD. Most approaches focus on quantitative changes of individual proteins such as tau and A2 in patient samples as biomarkers. These studies have led to a consensus that an increase in total and p-tau and a concomitant decrease in A21-42 in CSF may be indicative of neurodegeneration. However, these changes are not specific indicators of AD and may also occur in some other forms of dementia. Therefore, these biomarkers cannot be used for differential diagnosis of AD at early onset and to stage disease progression. The development of novel biomarkers based on the paradigm of protein-protein interactions, rather than on specific protein levels, may create opportunity for earlier and more specific diagnosis and disease monitoring for better patient management. Using the approach of measuring pathological interactions between proteins may provide urgently needed novel AD biomarkers. These biomarkers can also serve as drug targets for the identification of new medication therapies to treat AD and to monitor different therapeutic effects when used to treat AD. OLIGOMERIX is evaluating novel AD biomarkers based on soluble complexes containing tau oligomers and complexes containing both tau and A21-42. Preliminary feasibility studies with a limited number of CSF samples have indicated that tau oligomers and tau- A21-42 complexes are enhanced in CSF from AD compared to non-AD controls. ELISAs of different formats were developed to measure these parameters in CSF. The objective of this project is to expand the preliminary studies using a statistically significant number of clinical lumbar CSF samples that include severe, mild and age-matched non-AD controls to assess the potential of tau oligomers tau A2, and tau-apoE complexes as specific biomarkers for early detection and progression of AD. This work will be performed in collaboration with Drs. Richard Mayeux and Lawrence Honig at the Taub Institute for Research on Alzheimer's disease and the Aging Brain at Columbia University Medical Center. The specific aims of the proposed program are as follows: " Develop biomarker assays for AD measuring tau oligomers and complexes of tau with A2 or apoE in CSF " Conduct feasibility study of developed biomarker assays using clinical CSF samples Towards this end Dr. Honig will provide about 250 CSF samples for a statistically significant study of the biomarkers. OLIGOMERIX will perform ELISAs on de-identified blinded samples, and Dr. Honig will analyze the data. The biomarkers may be out-licensed to the pharmaceutical industry for clinical evaluation of compounds targeting tau oligomers, tau-A2, or tau-apoEcomplexes. Key Words Alzheimer's disease, biomarker, tau, A2, apoE, oligomer. PUBLIC HEALTH RELEVANCE: The proposed program is focused on the identification and development of novel biomarkers for Alzheimer's disease (AD), based on the paradigm of protein-protein interactions. Presently, AD biomarker studies are primarily focused on the quantitative changes in the levels of protein involved in AD etiology. In addition to AD, these changes may also occur in some other forms of dementia, therefore, are not specific indicators of AD. Here we propose to evaluate novel AD biomarkers based on soluble complexes containing key protein players in AD: tau, A21-42 and apoE. Our goal is to 1) develop biomarker assays to measure the interactions of tau protein with itself (tau oligomers), A2 or apoE in human CSF samples, 2) evaluate the feasibility of using tau oligomers, or tau complexes with A2 or apoE as biomarkers for AD using a significantly large number of CSF samples.