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

描述（由申请人提供）：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）被认为构成了AD的危险群体。2011年，美国阿尔茨海默病患者每年的医疗保健服务成本达到1830亿美元。目前还没有针对阿尔茨海默病患者的疾病改善疗法，而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。在这项研究中，SBIR DiamiR建议开发一种具有成本效益的微创测试，用于早期特异性检测AD和预测从轻度认知障碍（MCI）到AD痴呆的疾病进展。该测试将基于对血浆中无细胞miRNA的RT-PCR分析，这是一种简单的分析方法，可以在大多数临床实验室进行。该测试将有可能被用于(1)识别处于早期可逆性疾病阶段的患者，这些患者可以被招募用于临床试验；(2)监测患者对各种治疗的反应；(3)更好地规划疾病早期的临床护理。阿尔茨海默病早期的特点是海马和皮质的神经突和突触破坏。DiamiR假设，以下创新将允许在体外使用血浆中无细胞miRNA的定量分析来高度敏感地检测这些过程：(1)将海马神经突和突触中存在的脑富集miRNA作为潜在的生物标志物进行测试；(2)将生物标志物miRNA的浓度与位于非病理参与的细胞和脑区域的其他脑富集miRNA进行标准化，以补偿与AD无关但影响血浆中生物标志物miRNA浓度的因素。DiamiR的初步研究非常有希望：测量几种生物标志物和正常化miRNA的血浆浓度，如刚才所述，可以将MCI与年龄匹配的对照组区分，灵敏度和特异性均为85%，超过了阿尔茨海默氏症协会规定的目标。目前的I期研究探讨了MCI患者早期特异性检测AD的可行性。第一阶段的具体情况

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.