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

描述（由申请人提供）：在开发阿尔茨海默病（AD）的治疗方面的进展仍然很小，尽管该疾病影响65岁以上的八分之一的人，每年给美国经济带来超过2000亿美元的负担。一个重要因素是缺乏有效的AD诊断方法和量化研究新药的疗效。尽管PET探针在斑块中发现的淀粉样纤维成像方面取得了令人兴奋的进展，多年来为AD研究提供了一个重要的焦点，但斑块与认知丧失没有很好的相关性，不能提供疾病发作的及时指标，并且不再被认为是AD神经元损伤的最初原因。该项目解决了对探针的需求，该探针靶向在AD病理学中早期出现的分子，并负责启动神经元损伤。我们选择的目标是有毒的A？低聚物（A？O），制备了一种新型的分子MRI探针。有毒A？许多研究人员认为，Os是引发AD神经元损伤的初始阶段。证据显示A？在AD早期，骨开始积累，这可能是AD病理学的第一个指标。我们的直接目标是获得与5XFAD tg小鼠的概念证明，我们的MRI探头（NU4MNS）将跟踪A？体内组织学符合预期。NU4MNS包括水稳定的磁性纳米结构（MNS），其作为与我们团队的NU4单克隆抗体缀合的强大MRI造影剂。NU4亲本抗体选择性靶向A？Os具有高亲和力，鼻内给药时，它很容易靶向海马A？小鼠AD模型中的OS。NU4MNS探头在初步研究中显示出出色的MRI诊断潜力。探针保留充分的能力，选择性结合A？Os，并且它可以通过MRI信号区分体外人AD脑样品和对照。该项目将进行三项研究，以扩大我们成功的初步研究结果，并推进我们的长期临床目标成像A？MRI显示AD患者的骨密度。（研究1）进行原型测定A？使用来自5X FAD小鼠模型的脑切片的O依赖性MRI信号。（研究2）优化探针向AD和对照小鼠脑的鼻内递送。（研究3）获得概念证明，即可以使用NU4MNS MRI探针鉴定具有AD病理学的小鼠，并且该探针可以确定降低A？给药动物中的Os。我们的成像目标建立在其他团队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的临床成像成为可能。该项目有望通过开发一种新的探针来检测神经元损伤性A？在小鼠病理学的早期阶段，通过实验药物监测毒素减少。开发针对神经毒素A的可靶向纳米结构？Os有可能提供一种MR成像模式，用于评估研究性新药（IND）的疾病改善疗效，并最终提供早期AD诊断和后续疾病管理。

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 A? oligomer (A?O), for which we have prepared a novel molecular MRI probe. Toxic A?Os are regarded by many researchers as instigating the initial stages of AD neuron damage. Evidence indicates A?Os 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 A?Os 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 A?Os with high affinity and, when delivered intranasally, it readily targets hippocampal A?Os 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 A?Os, 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 A?Os in AD patients by MRI. (Study 1) Carry out prototype assays for A?O-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 A?Os 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 A?Os at early stages of mouse pathology and monitor toxin reduction by an experimental drug. Development of targetable nanostructures specific for neurotoxic A?Os 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.