Early detection of Alzheimer's (MCI stage): Analysis of plasma cell-free miRNA

描述(申请人提供)：阿尔茨海默病(AD)是最常见的神经退行性疾病(ND)。目前在美国有540万AD患者；相关的医疗费用为每年2000亿美元。在65岁以上的人中，有10-20%患有轻度认知障碍(MCI)，其中估计每年有15%的人进展为痴呆症。尽管目前尚无治疗阿尔茨海默病的方法，但对近期临床试验数据的分层分析显示，早期患者的治疗效果令人振奋。因此，迫切需要准确的无创性、高性价比的诊断方法来进行初步筛查。Diamir基于对血浆中循环的脑富集型microRNAs(MiRNAs)的分析，为AD和其他NDS的早期检测和监测开发了创新的测试。最近，我们鉴定并验证了6对miRNA(“miR-132”和“miR-134”家族)的生物标志物特征，能够区分MCI和年龄匹配的对照，准确率高达96%。在SBIR第一阶段研究中，其他几对miRNA已显示出预测MCI向AD转变以及将MCI和AD与帕金森病(PD)区分开来的希望。目前的SBIR第二阶段研究旨在从前瞻性和回溯性研究的更大、特征良好的异质队列患者的血浆样本中测试Diamir确定的候选miRNA生物标记物，以验证用于AD早期特异性检测的生物标记物miRNA签名。具体目标包括确定如何检测早期MCI和AD，以及是否可以可靠地预测从MCI前期和MCI到AD的进展；评估miRNA生物标记物与AD现有生物标记物(神经成像和脑脊液生物标记物)的相关性；以及验证用于区分AD与其他NDS-PD、额颞叶痴呆(FTLD)和肌萎缩侧索硬化症(ALS)的生物标记物miRNA签名。Diamir发现生物标记物的方法所依据的假设如下：由于NDS的早期阶段以不同大脑区域和神经元类型中的轴突和突触破坏为特征，我们假设，用于检测AD早期阶段、预测前MCI和MCI进展为痴呆以及AD与其他NDS的区别的miRNA生物标记物可以使用生物标记物miRNA对来定义，每对miRNA由(1)miRNA组成，这些miRNA富含在受病理影响的大脑区域(AD的海马区、PD的中脑、ALS的运动神经元等)。也存在于神经突起和突触中；以及(2)存在于未参与病理的细胞和脑区的其他脑丰富的miRNAs，用作正常化，以补偿与病理无关的因素。其他潜在有用的miRNA对包括不在大脑中富含但参与进行性疾病阶段(例如炎症、细胞凋亡)特征的过程的miRNAs；以及富含大脑的miRNAs。基于本文验证的miRNA签名的实验室开发测试(LDT)将根据CLIA指南开发，并用于筛选患者进行临床试验。这些测试将帮助研究人员和临床医生检测MCI并预测MCI是否会进展为AD或其他NDS。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common neurodegenerative disease (ND). Currently in the US there are 5.4M AD patients; associated healthcare cost is $200B per year. 10-20% of people age 65+ have Mild Cognitive Impairment (MCI) of which estimated 15% progress to dementia annually. Although no disease- modifying therapy for AD is available, stratified analysis of data from recent clinical trials revealed promising results for early stage patients. Thus, there is a great need for accurate noninvasive cost-effective diagnostics for primary screening. DiamiR develops innovative tests for early detection and monitoring of AD and other NDs based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma. Recently we identified and validated a biomarker signature of 6 miRNA pairs ("miR-132" and "miR-134" families) capable of differentiating MCI from age-matched control with up to 96% accuracy. In the SBIR Phase I study several additional miRNA pairs have shown promise for prediction of MCI to AD transition and differentiation of MCI and AD from Parkinson's disease (PD). The present SBIR Phase II study aims to test candidate miRNA biomarkers identified at DiamiR in plasma samples from larger, well-characterized, heterogeneous cohorts of patients from both prospective and retrospective studies, so as to validate biomarker miRNA signatures for early specific detection of AD. Specific aims include determining how early MCI and AD can be detected, and whether progression from pre-MCI and MCI to AD can be reliably predicted; assessing correlation of the miRNA biomarkers with existing biomarkers of AD (neuroimaging and cerebrospinal fluid biomarkers); and validation of biomarker miRNA signatures for differentiation of AD from other NDs - PD, Frontotemporal Lobe Dementia (FTLD), and Amyotrophic Lateral Sclerosis (ALS). The hypothesis underlying DiamiR's approach to biomarker discovery is as follows: since early stages of NDs are characterized by neurite and synapse destruction in distinct brain areas and neuron types, we hypothesize that miRNA biomarkers for detection of early stages of AD, prediction of pre-MCI and MCI progression to dementia, and differentiation of AD from other NDs can be defined using biomarker miRNA pairs, with each pair consisting of (1) miRNAs which are enriched in brain regions affected by a pathology (hippocampus for AD, midbrain for PD, motor neurons for ALS, etc.) and also present in neurites and synapses; and (2) other brain-enriched miRNAs present in cells and brain regions not involved in the pathology, used as normalizers, so as to compensate for factors not re- lated to the pathology. Additional potentially useful miRNA pairs consist of miRNAs not enriched in the brain, but involved in the processes characteristic of progressive disease stages (e.g. inflammation, apoptosis); and of brain-enriched miRNAs. Lab-Developed Tests (LDTs) based on the miRNA signatures validated herein will be developed under CLIA guidelines and used to screen patients for clinical trials. The tests will assist researchers and clinicians with detecting MCI and predicting whether MCI will progress to AD or other NDs.