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

一种用于早期阿尔茨海默病诊断的新型纳米粒子分子 MRI 探针

• 批准号: 8842908
• 负责人: WILLIAM L KLEIN
• 金额: $ 18.73万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842908
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid Fibrils; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Binding; Biological Assay; Brain; Brain imaging; Cell Size; Cell surface; Cells; Clinical; Contrast Media; Development; Diagnosis; Diagnostic; Disease; Disease Management; Dose; Drug Monitoring; Early Diagnosis; Epitopes; Evaluation; Foundations; Goals; Health; Hippocampus (Brain); Hour; Human; Image; Imaging technology; Impaired cognition; In Vitro; Individual; Investigational Drugs; Life; Magnetic Resonance Imaging; Magnetism; Measurement; Memory; Methods; Molecular; Molecular Conformation; Monitor; Monoclonal Antibodies; Mus; Nanostructures; Neoplasm Metastasis; Neurology; Neurons; Neurotoxins; Nose; Oncologist; Onset of illness; Outcome; Parents; Pathology; Patients; Persons; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Protocols documentation; Published Comment; Recording of previous events; Research Personnel; Resources; Sampling; Senile Plaques; Signal Transduction; Staging; Technology; Testing; Therapeutic; Time; Toxin; aqueous; base; beta-site APP cleaving enzyme 1; cancer cell; disease diagnosis; disorder control; drug efficacy; imaging modality; in vivo; inhibitor/antagonist; meetings; monomer; mouse model; nanoparticle; neoplastic cell; neurotoxic; novel; novel strategies; prototype; research study; success

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.

描述（由申请人提供）：开发阿尔茨海默氏病（AD）治疗的进展仍然很少，尽管这种疾病影响了八分之一的人，超过65人，每年超过2000亿美元的经济负担。一个重要的因素是缺乏用于AD诊断的有效方法以及量化研究新药的功效。尽管在斑块中发现的淀粉样蛋白纤维中的PET探针方面令人兴奋的进展，这些斑块在多年来为AD研究提供了重要的重点，但斑块与认知损失没有很好的相关性，不再提供及时的疾病发作指标，并且不再被视为AD Neuron损害的初始原因。该项目解决了针对靶向AD病理早期分子并负责启动神经元损害的探针的需求。我们选择的目标是有毒的A？低聚物（a？o），为此我们准备了一种新型的分子MRI探针。许多研究人员认为有毒的A OS是煽动AD神经元损伤的初始阶段。证据表明，A OS开始在早期AD中积累，也许是AD病理学的第一个指标。我们的近期目标是使用5xFAD TG鼠标获得概念证明，我们的MRI探针（NU4MN）将按照预期的方式跟踪体内的？OS。 NU4MNS包括水稳定的磁性纳米结构（MNS），它们充当强大的MRI对比剂，并与我们团队的NU4单克隆抗体偶联。 NU4母体抗体选择性地靶向具有高亲和力的A OS，并且在鼻内传递时，它很容易靶向鼠标AD模型中的海马A？OS。 NU4MNS探针在初步研究中显示出了MRI诊断的出色潜力。该探针保留有选择性结合A？OS的全部能力，并且可以通过MRI信号将体外人类AD脑样品与对照区分开。该项目将进行三项研究，以扩大我们成功的初步发现，并将探测器推向MRI在AD患者中成像A OS的远程临床目标。 （研究1）使用5倍FAD小鼠模型的脑部进行了对O依赖性MRI信号的原型测定。 （研究2）优化鼻内探针向AD和对照小鼠的脑部递送。 （研究3）获得概念证明，即可以使用NU4MNS MRI探测器鉴定具有AD病理学的小鼠，并且该探针可以确定在降低治疗动物中A？OS方面的药物疗效。我们的成像目标是基于其他团队具有里程碑意义的突破，这使得在阿尔茨海默氏病患者中可以在临床上成像淀粉样蛋白斑块。预计该项目将通过开发新的探针来提高成像资源，可以在小鼠病理学的早期阶段检测神经元损害A OS，并通过实验药物减少毒素。针对神经毒性A的特定目标纳米结构的开发具有提供MR成像方式的潜力，用于评估研究性新药（IND）的疾病改良功效，并最终提供早期AD诊断以及随后的疾病管理。