A novel, nanoparticle-based molecular MRI probe for early Alzheimer's diagnostics

描述（由申请人提供）：尽管阿尔茨海默病（AD）影响着每8个65岁以上的人中就有1人，每年给美国经济造成超过2000亿美元的负担，但开发阿尔茨海默病（AD）治疗方法的进展仍然很小。一个重要的因素是缺乏有效的阿尔茨海默病诊断方法和量化正在研究的新药疗效的方法。尽管PET探针在斑块中发现的淀粉样原纤维成像方面取得了令人兴奋的进展，多年来一直是阿尔茨海默病研究的重要焦点，但斑块与认知丧失的相关性并不好，不能提供疾病发病的及时指标，也不再被认为是阿尔茨海默病神经元损伤的初始原因。该项目解决了对一种靶向在阿尔茨海默病病理早期出现并负责启动神经元损伤的分子的探针的需求。我们选择的目标是有毒的a β低聚物（a β o），为此我们准备了一种新的分子MRI探针。毒性a β o被许多研究者认为是阿尔茨海默病神经元损伤的初始阶段。有证据表明a β o在早期AD开始积累，这可能是AD病理的第一个指标。我们的直接目标是通过5XFAD tg小鼠获得概念证明，我们的MRI探针（NU4MNS）将像预测的那样在体内跟踪a β o。NU4MNS包含水稳定磁性纳米结构（MNS），作为强大的MRI造影剂，已偶联到我们团队的NU4单克隆抗体上。NU4亲本抗体以高亲和力选择性靶向a - β o，在小鼠AD模型中，当经鼻给药时，它很容易靶向海马a - β o。NU4MNS探针在初步研究中显示出了出色的MRI诊断潜力。该探针保留了选择性结合a - β o的全部能力，并且可以通过MRI信号区分体外人AD脑样本和对照组。该项目将进行三项研究，以扩展我们成功的初步发现，并推进我们通过MRI成像AD患者a β o的长期临床目标。（研究1）利用5X FAD小鼠模型的脑切片对a β o依赖的MRI信号进行原型分析。（研究2）优化阿尔茨海默病小鼠及对照小鼠的鼻内给药探针。（研究3）获得概念证明，使用NU4MNS MRI探针可以识别AD病理小鼠，并且该探针可以确定药物在治疗动物中降低a β o的功效。我们的成像目标建立在其他团队取得的里程碑式突破的基础上，这些突破使阿尔茨海默病患者的淀粉样斑块临床成像成为可能。该项目有望通过开发一种新的探针，在小鼠病理的早期阶段检测神经元损伤的a β o，并通过一种实验药物监测毒素的减少，从而推进成像资源。神经毒性a β o特异性靶向纳米结构的开发有可能为评估研究新药（INDs）的疾病改善效果提供一种磁共振成像模式，并最终提供早期AD诊断和随后的疾病管理。

DESCRIPTION (provided by applicant): Progress in developing a treatment for Alzheimer's disease (AD) remains minimal, despite the disease affecting one in eight persons over 65 at a burden to the US economy of over $200 billion per year. A significant factor is the lack of effective methods for AD diagnosis and for quantifying the efficacy of investigational new drugs. Despite exciting progress with PET probes in imaging amyloid fibrils found in plaques, which have provided an important focus for AD studies over many years, plaques do not correlate well with cognitive loss, do not offer a timely indicator of disease onset, and are no longer regarded as the initial cause of AD neuron damage. This project addresses the need for a probe that targets molecules that appear earlier in AD pathology and that are responsible for initiating neuron damage. Our choice of target is the toxic Aβ oligomer (AβO), for which we have prepared a novel molecular MRI probe. Toxic AβOs are regarded by many researchers as instigating the initial stages of AD neuron damage. Evidence indicates AβOs begin to accumulate in early AD, perhaps the first indicator of AD pathology. Our immediate goal is to obtain proof of concept with the 5XFAD tg mouse that our MRI probe (NU4MNS) will track AβOs in vivo as predicted. NU4MNS comprises aqueous-stable magnetic nanostructures (MNS), which act as powerful MRI contrast agents that have been conjugated to our team's NU4 monoclonal antibody. The NU4 parent antibody selectively targets AβOs with high affinity and, when delivered intranasally, it readily targets hippocampal AβOs in a mouse AD model. The NU4MNS probe has shown outstanding potential for MRI diagnostics in preliminary studies. The probe retains full ability to selectively bind AβOs, and it can distinguish in vitro human AD brain samples from controls by MRI signal. The project will undertake three studies to extend our successful initial findings and advance the probe toward our long-range clinical goal of imaging AβOs in AD patients by MRI. (Study 1) Carry out prototype assays for AβO-dependent MRI signals using brain sections from the 5X FAD mouse model. (Study 2) Optimize intranasal delivery of probe to brain of AD and control mice. (Study 3) Obtain proof of concept that mice with AD pathology can be identified using the NU4MNS MRI probe, and that the probe can determine drug efficacy in lowering AβOs in treated animals. Our imaging goal builds on landmark breakthroughs from other teams that have made it possible to clinically image amyloid plaques in Alzheimer's patients. This project is expected to advance imaging resources by developing a new probe can detect neuron- damaging AβOs at early stages of mouse pathology and monitor toxin reduction by an experimental drug. Development of targetable nanostructures specific for neurotoxic AβOs has potential to provide an MR imaging modality for evaluating the disease-modifying efficacy of investigational new drugs (INDs) and ultimately deliver early-stage AD diagnosis and subsequent disease management.