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.

2015 年，美国估计有 530 万人患有阿尔茨海默病 (AD)， 多达 50% 的人未被诊断（阿尔茨海默病协会 2015）提出 AD 的三个阶段。 （国家老龄化研究所和阿尔茨海默病协会 2011 年）：临床前 AD，轻度认知障碍 AD 引起的 MCI 和 AD 引起的痴呆 临床前阶段建议在 20 年前或更早开始。 如今，许多研究人员相信减缓或阻止 AD 的治疗方法将是最有效的。 然而，如果在临床前或 MIC 阶段施用，则需要新的生物标志物测试来识别。 这些生物标志物测试对于监测治疗效果也至关重要。 目前 AD 的生物标志物测试基于总淀粉样蛋白 (Aβ) 的水平，主要是单体， 脑脊液 (CSF)、CSF 中 tau 蛋白和磷酸化 tau 蛋白的水平，或原纤维淀粉样斑块的水平 然而，许多研究人员现在将非原纤维 Aβ 寡聚物 (Aβo) 视为与大脑中的相比。 单体或原纤维 Aβ，作为导致急性认知缺陷并诱发慢性认知障碍的主要 Aβ 毒素 AD 的神经元变性（tau 异常、突触丢失、氧化损伤等） A 非侵入性。 检测和量化 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测试 以及用于监测治疗效果的初步研究表明，Aβo 选择性抗体-正电子。 发射断层扫描 (PET) 探针可以实现 Aβo 的体内检测和定量。 ACU193 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 在 AD 小鼠模型中，Aβo 与单体和原纤维 A 相比，ACU193 穿过血脑屏障并 在大脑中与 Ao 形成复合物，表现出优异的药代动力学、生物分布和大脑功能。 蛋白质结合研究显示出对 Aβo 的出色选择性。 猴子毒性研究表明 ACU193 具有出色的安全性，因此，ACU193 是理想的候选药物。 用于测试 Aβo 抗体 PET 探针在 Aβo 体内检测和定量方面的潜在用途。 这一阶段 1 STTR 应用的目标是准备和优化 ACU193-PET 探针和 证明它可以提供来自转基因 AD 小鼠的灵敏且选择性的体外 Aβo 依赖性信号 模型组织和人类 AD 脑组织的基本假设是敏感且高度 Aβo。 如果体外灵敏度和选择性良好，可以使用 64Cu 标记的 ACU193 制作选择性 PET 探针。 第一阶段研究还将评估转基因 AD 小鼠体内探针的敏感性 该计划的总体成功将为检测和量化提供一种非侵入性方法。 Aβo 体内，并支持其作为 AD 诊断工具的开发，用于监测疾病进展和 治疗效果并作为一种研究工具，可以更好地了解 AD 的病因学。