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：目前美国有540万人患有AD，多达8000万美国人(55岁以上)被认为是AD的风险群体。2011年，美国AD患者的年医疗服务成本达到1830亿美元。目前，阿尔茨海默病患者尚无疾病修正疗法，新疗法的开发在很大程度上由于缺乏有效的疾病早期诊断和监测方法而变得复杂。在这项SBIR中，Diamir建议开发一种具有成本效益的微创测试，用于AD的早期特异性检测和从轻度认知障碍(MCI)到AD痴呆的疾病进展预测。这项测试将基于对血浆中无细胞miRNA的RT-PCR分析-这是一种简单的测试，可以在大多数临床实验室进行。这项测试可能被用于(1)识别可被招募用于临床试验的EARL可逆期患者，(2)监测患者对各种治疗的反应，以及(3)更好地计划疾病早期的临床护理。早期阿尔茨海默病的特点是海马区和皮质区的突触和突触破坏。Diamir假设，通过对血浆中无细胞miRNA的定量分析，下列创新将能够在体外高度灵敏地检测到这些过程：(1)存在于海马神经突起和突触中的脑富集型miRNA将被测试为潜在的生物标记物，以及(2)位于细胞和大脑不参与病理的区域的其他脑富集型miRNA的浓度将被归一化，以补偿与AD无关但影响血浆中生物标记物miRNA浓度的因素。Diamir的初步研究非常有希望：通过测量几种生物标记物和正常剂miRNA的血浆浓度，可以将MCI与年龄匹配的对照组区分开来，灵敏度和特异度均为85%，超过了阿尔茨海默氏症协会指定的目标。目前的I期研究致力于在MCI患者中早期特异性检测AD的可行性。第一阶段的具体情况 目的是：(1)评估检测将发展为AD痴呆的MCI患者的可行性；(2)证明使用某些大脑区域丰富的miRNA可以有效区分不同的神经退行性疾病。作为第二阶段，Diamir将进行一项大型纵向研究，旨在验证初步研究(早期MCI检测)和第一阶段中确定的生物标记物/正常化集合，并测试这些集合在无症状受试者中检测MCI的效用，以及预测和监测MCI向AD痴呆的转变。所有数据分析将使用Diamir开发的定制计算机程序进行。随着项目的成熟，Diamir将探索与一家更大的诊断公司合作，将测试推向市场，并与制药公司合作，探索将该技术用于患者分层和配套诊断。

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most common neurodegenerative disease: 5.4 million people are currently living with AD in the US, and up to 80 million Americans (over 55 years old) are considered to constitute the risk group for AD. In 2011, the annual cost of healthcare services for AD patients in the US reached $183 billion. There are currently no disease-modifying therapies available to AD patients, and the development of new therapeutics is complicated in large part by the absence of effective methods for early diagnosis and monitoring of the disease. In this SBIR DiamiR proposes to develop a cost-effective minimally invasive test for early specific detection of AD and prediction of disease progression from Mild Cognitive Impairment (MCI) to AD dementia. The test will be based on RT-PCR analysis of cell-free miRNA in plasma - a simple assay, which can be performed in most clinical labs. The test will potentially be used (1) to identify patients in earl, reversible stages of the disease that can be recruited for clinical trials, (2) to monitor patients response to various treatments, and (3) to better plan clinical care in earlier stages of the disease. Early stages of AD are characterized by neurite and synapse destruction in hippocampus and cortex. DiamiR hypothesizes that the following innovations will allow highly sensitive detection of these processes in vitro using quantitative analysis of cell-free miRNA in plasma: (1) brain-enriched miRNA present in neurites and synapses of hippocampus will be tested as potential biomarkers, and (2) concentrations of biomarker miRNA will be normalized per other brain-enriched miRNA, located in cells and brain areas not involved in the pathology, so as to compensate for factors not related to AD yet affecting concentrations of biomarker miRNA in plasma. DiamiR's preliminary studies have been highly promising: measurement of plasma concentrations of several biomarker and normalizer miRNA, selected as just described, allowed differentiating MCI from the age- matched control with both sensitivity and specificity >85%, exceeding the targets specified by the Alzheimer's Association. The present Phase I study addresses feasibility of early specific detection of AD in MCI patients. The Phase I specific aims are: (1) assess feasibility of detecting MCI patients that will progress to the AD dementia; and (2) demonstrate that using miRNA enriched in certain brain areas allows for effective differentiation between distinct neurodegenerative diseases. As Phase II, DiamiR will conduct a large longitudinal study designed to validate the biomarker/normalizer sets identified in preliminary studies (early MCI detection) and Phase I, and to test the utility of these sets for detecting MCI in asymptomatic subjects, as well as for predicting and monitoring MCI to AD dementia transition. All data analysis will be performed using custom-built computer program developed at DiamiR. As the project matures, DiamiR will explore partnering with a larger diagnostics firm to bring the test to market, and with pharmaceutical companies to explore use of the technology for patient stratification and as companion diagnostics.