Development of a non-fibrillic amyloid-beta oligomer selective positron emission tomography imaging diagnostic for Alzheimer.

开发用于阿尔茨海默氏症的非纤维状淀粉样蛋白-β寡聚物选择性正电子发射断层扫描成像诊断。

• 批准号: 9202960
• 负责人: WILLIAM L KLEIN
• 金额: $ 22.22万
• 依托单位: ACUMEN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202960
• 关键词: Acute; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Antibodies; Autoradiography; Binding; Binding Proteins; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Brain; Cause of Death; Cerebrospinal Fluid; Chronic; Cognitive deficits; Complex; Confocal Microscopy; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Disease Progression; Drug Kinetics; Early Diagnosis; Etiology; Exhibits; Failure; Goals; Human; Image; Impaired cognition; In Vitro; Individual; Investigational Drugs; Label; Life; Measurement; Measures; Medical; Memory; Methods; Mission; Monitor; Monkeys; Mus; National Institute on Aging; Nerve Degeneration; Outcome; Pathology; Patient Monitoring; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phase; Play; Positron-Emission Tomography; Proteins; Public Health; Research; Research Personnel; Role; Safety; Sampling; Senile Plaques; Signal Transduction; Small Business Technology Transfer Research; Societies; Spinal Puncture; Staging; Symptoms; Synapses; Targeted Research; Techniques; Technology; Testing; Therapeutic; Toxic effect; Toxin; Transgenic Organisms; United States; Work; abeta oligomer; aged; base; brain tissue; clinical Diagnosis; cross reactivity; effective therapy; human tissue; humanized monoclonal antibodies; imaging probe; in vivo; mild cognitive impairment; monomer; mouse model; novel therapeutics; oxidative damage; phase 1 study; pre-clinical; prognostic; programs; success; tau Proteins; tau mutation; tau-1; tool; treatment effect

In the United States in 2015 an estimated 5.3 million people suffered from Alzheimer’s disease (AD), with as many as 50% being undiagnosed (Alzheimer’s Association 2015). Three stages of AD are proposed (National Institute on Aging and the Alzheimer’s Association 2011): preclinical AD, mild cognitive impairment (MCI) due to AD, and dementia due to AD. The preclinical stage is proposed to begin 20 or more years before symptoms appear. Today, many researchers believe that treatments to slow or stop AD will be most effective if administered during the preclinical or MIC stages. However, new biomarker tests are needed to identify individuals at these early stages. These biomarker tests will also be essential for monitoring treatment effects. Current biomarker tests for AD are based on the levels of total amyloid beta (Aβ), mainly monomer, in cerebrospinal fluid (CSF), levels of tau and phosphorylated tau in CSF, or the levels of fibrillic amyloid plaques in the brain. However, many researchers now regard non-fibrillic Aβ oligomers (Aβo), in contrast to monomeric or fibrillic Aβ, as the primary Aβ toxins that cause acute cognitive deficits and induce the chronic neuronal degeneration of AD (tau abnormalities, synapse loss, oxidative damage, etc.). A non-invasive method to detect and quantify Aβo could provide a valuable biomarker test to identify early stage AD patients and for monitoring the effect of therapies. Preliminary studies suggest that an Aβo selective antibody-positron emission tomography (PET) probe may enable the in vivo detection and quantification of Aβo. ACU193 is a proprietary, affinity matured, humanized, monoclonal antibody exhibiting high selectivity for Aβo versus monomeric and fibrillic A. In AD mouse models, ACU193 crosses the blood-brain barrier and forms complexes with Ao in the brain. ACU193 exhibits excellent pharmacokinetics, biodistribution and brain penetration in four animal species. Protein binding studies show excellent selectivity for Aβo. Exploratory toxicity studies in monkeys reveal an excellent safety profile for ACU193. Thus, ACU193 is an ideal candidate for testing the potential utility of an Aβo antibody PET probe for the in vivo detection and quantification of Aβo. The objective of this Phase 1 STTR application is to prepare and optimize an ACU193-PET probe and demonstrate that it provides a sensitive and selective in vitro Aβo-dependent signal from transgenic AD mouse model tissues and human AD brain tissues. The underlying hypothesis is that a sensitive and highly Aβo selective PET probe can be made using ACU193 labeled with 64Cu. If in vitro sensitivity and selectivity are achieved, the Phase 1 study will also evaluate the sensitivity of the probe in vivo in a transgenic AD mouse mode. Overall success in this program would provide a non-invasive method for detecting and quantifying Aβo in vivo, and support its development as an AD diagnostic tool for monitoring disease progression and the effects of treatment and as a research tool that would enable a better understanding of the etiology of AD.

在美国，2015年估计有530万人患有阿尔茨海默病（AD）， 其中多达50%未被诊断（阿尔茨海默氏症协会2015）。提出了AD的三个阶段 （国家老龄化研究所和阿尔茨海默氏症协会2011）：临床前AD，轻度认知障碍 (MCI)以及AD引起的痴呆。临床前阶段建议在20年或更长时间之前开始 症状出现。今天，许多研究人员认为，减缓或停止AD的治疗将是最有效的 如果在临床前或MIC阶段给药。然而，需要新的生物标志物测试来识别 在这些早期阶段。这些生物标志物检测对于监测治疗效果也至关重要。 目前AD的生物标志物测试是基于总淀粉样蛋白β（Aβ）的水平，主要是单体， 脑脊液（CSF）中tau和磷酸化tau的水平，或纤维状淀粉样斑块的水平 在大脑中。然而，许多研究人员现在认为非纤维状Aβ寡聚体（Aβo）， 单体或纤维状Aβ，作为主要的Aβ毒素，可引起急性认知缺陷和诱发慢性 AD的神经元变性（tau异常、突触损失、氧化损伤等）。一种非侵入性 一种检测和定量Aβo的方法可以为识别早期AD患者提供有价值的生物标志物检测 以及用于监测治疗的效果。初步研究表明，Aβo选择性抗体-正电子 发射断层扫描（PET）探头可以实现Aβo的体内检测和定量。 ACU 193是一种专有的、亲和力成熟的人源化单克隆抗体，具有高选择性 与单体和纤维状A β相比。在AD小鼠模型中，ACU 193穿过血脑屏障， 在大脑中与A β形成复合物。ACU 193具有优异的药代动力学、生物分布和脑组织分布。 在四种动物中的渗透。蛋白结合研究显示对Aβo具有极佳的选择性。探索性 在猴子中的毒性研究揭示了ACU 193的极好的安全性特征。因此，ACU 193是理想的候选者 用于测试Aβo抗体PET探针用于体内检测和定量Aβo的潜在效用。 该第1阶段STTR应用的目的是制备和优化ACU 193-PET探头， 证明它提供了一个敏感的和选择性的体外Aβ o依赖性信号从转基因AD小鼠 模型组织和人AD脑组织。潜在的假设是，一个敏感的和高度Aβo 用64 Cu标记的ACU 193可制成选择性PET探针。如果体外灵敏度和选择性 实现后，1期研究还将在转基因AD小鼠中评价探针的体内灵敏度 模式这项计划的全面成功将提供一种非侵入性的方法，用于检测和定量 Aβo在体内的表达，并支持其作为监测疾病进展的AD诊断工具的发展， 作为一种研究工具，将使人们能够更好地了解AD的病因。