Brain-enriched microRNAs detectable in plasma as biomarkers of Alzheimer's Disease

总结 在65岁及以上的美国人中，十分之一患有阿尔茨海默病（AD）。由于AD开始于长时间的，超过 10年之久，无症状阶段，越来越多的公司正在开发新的疗法，旨在 早期干预AD和相关形式的痴呆症的进展。因此，非常需要最低限度地 侵入性诊断工具，用于疾病早期个体的初步筛查。DiamiR拥有 开发了一种平台技术，用于检测、预后和监测不同阶段（从临床前 阶段痴呆）的AD的基础上有针对性的选择和分析的脑富集和炎症- 在血浆中循环的相关microRNAs（miRNAs）。与领先的学术阿尔茨海默氏症 DiamiR已经产生了大量的数据，这些数据支持使用miRNA生物标志物 在疾病的不同阶段检测AD。该数据包括临床诊断的轻度 认知功能障碍（MCI），准确率为95%，AD与其他神经退行性疾病的鉴别 准确率≥80%，识别认知正常受试者，随后进展为MCI，准确率为75%。 精度基于对1,000多个充分表征的血浆样本的分析，我们定义了24种miRNA， 诊断测试，CogniMIRTM。当前商业化准备计划（CRP）的目标是 开发符合临床实验室改进修正案的临床就绪实验室开发检测（LDT） （CLIA）用于检测临床前AD、MCI和AD的指南。在正在进行的IIB期研究中，我们与 Roskamp研究所和Thermo Fisher Scientific分析多个预分析因素，以最大限度地减少 可变性并增加测定的灵敏度和再现性。我们优化了血液采集的流程， 血浆制备和miRNA提取。此外，我们还制定了详细的工作流程， 24-miRNA分类器。在目前的CRP项目中，我们将与Interpace Biosciences合作， 在符合CLIA标准的实验室中进行测试。以下分析 验证，我们将进行多中心双盲横断面临床研究，以评估测试性能 用于检测临床前AD、MCI和AD的代表性老年受试者， 在美国的各种阿尔茨海默病中心。如果项目成功，新的土地开发队将包括 CogniMIRTM可立即用于帮助筛选MCI/AD临床试验的患者。一旦CogniMIRTM 在使用来自异质性队列的15，000 - 20，000例患者样本进行验证后，我们将广泛启动该测试 老年病学家/神经学家和其他从事AD治疗和护理的医疗专业人员。

SUMMARY One in 10 Americans aged 65 and older have Alzheimer’s disease (AD). Since AD begins with a prolonged, over 10 year-long, asymptomatic stage, a growing number of companies are developing new therapies that aim to intervene early in the progression of AD and related forms of dementia. There is thus a great need for minimally invasive diagnostic tools for primary screening of individuals with early stages of the disease. DiamiR has developed a platform technology for detection, prognosis, and monitoring of different stages (from the preclinical stage to dementia) of AD based on targeted selection and analysis of brain-enriched and inflammation- associated microRNAs (miRNAs) circulating in blood plasma. Working with leading academic Alzheimer’s Disease Centers, DiamiR has produced a large amount of data, which supports the use of miRNA biomarkers for detection of AD at different stages of the disease. This data include detection of clinically diagnosed mild cognitive impairment (MCI) with accuracy of 95%, differentiation of AD from other neurodegenerative diseases with ≥80% accuracy, and identification of cognitively normal subjects who would later progress to MCI with 75% accuracy. Based on an analysis of over 1,000 well-characterized plasma samples, we defined 24 miRNAs for a diagnostic test, CogniMIRTM. The objective of the current Commercialization Readiness Program (CRP) is to develop a clinic-ready lab-developed test (LDT) compliant with Clinical Laboratory Improvement Amendments (CLIA) guidelines for detection of preclinical AD, MCI, and AD. In the ongoing Phase IIB study, we worked with the Roskamp Institute and Thermo Fisher Scientific to analyze multiple pre-analytical factors in order to minimize variability and increase sensitivity and reproducibility of the assay. We optimized the protocol for blood collection, plasma preparation, and miRNA extraction. Further, we have developed a detailed workflow for the analysis of 24-miRNA classifier. In the present CRP project, in partnership with Interpace Biosciences we will finalize assay protocol for the clinical setting and implement the test in a CLIA-compliant laboratory. Following analytical validation, we will perform a multi-center double-blinded cross-sectional clinical study to assess test performance for detection of preclinical AD, MCI, and AD among representative elderly subjects seen at geographically diverse Alzheimer’s Disease Centers in the US. Provided the project is successful, the new LDT comprising CogniMIRTM could be immediately used to help screen patients for MCI/AD clinical trials. Once the CogniMIRTM test is validated with 15,000-20,000 patient samples from heterogeneous cohorts, we will broadly launch the test to gerontologists/neurologists and other medical professionals engaged in AD treatment and care.