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2015年美国，估计有530万人患有阿尔茨海默氏病（AD）， 多达50％的人未被诊断（阿尔茨海默氏症协会，2015年）。提出了三个阶段的广告 （美国国家老龄研究所和阿尔茨海默氏症协会2011）：临床前广告，轻度认知障碍 （MCI）由于AD和由于AD而引起的痴呆症。提议在20年或更长时间之前开始临床前阶段 症状外观。如今，许多研究人员认为，放慢或停止广告的治疗方法将是最有效的 如果在临床前或麦克风阶段执行。但是，需要新的生物标志物测试来识别 个人处于这些早期阶段。这些生物标志物测试也对监测治疗效果至关重要。 当前的AD生物标志物测试基于总淀粉样β（Aβ）的水平，主要是单体， 脑脊液（CSF），CSF中的Tau和磷酸化tau水平，或原纤维淀粉样蛋白斑的水平 在大脑中。然而，许多研究人员现在考虑了非原纤维Aβ低聚物（AβO），与 单体或原纤维Aβ，作为引起急性认知缺陷并诱导慢性认知缺陷的主要Aβ毒素 AD的神经元变性（TAU异常，突触丧失，氧化损伤等）。无创的 检测和量化AβO的方法可以提供有价值的生物标志物测试以识别早期AD患者 并用于监测疗法的作用。初步研究表明AβO选择性抗体 - 蛋白质 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，亲和力成熟，人性化的单克隆抗体，具有高选择性 用于AβO与单体和原纤维A。在AD鼠标模型中，ACU193越过血脑屏障 在大脑中与AO形成复合物。 ACU193表现出出色的药代动力学，生物分布和大脑 四种动物物种的渗透。蛋白质结合研究表现出对AβO的极好选择性。探索性 猴子中的毒性研究揭示了ACU193的出色安全性。那就是ACU193是理想的候选人 用于测试AβO抗体PET探针对体内检测和AβO定量的潜在效用。 该阶段1 STTR应用的目的是准备和优化ACU193-PET探针，并且 证明它从转基因AD小鼠提供了灵敏的体外AβO依赖性信号 建模组织和人类AD脑组织。潜在的假设是敏感且高度的AβO 可以使用用64CU标记的ACU193进行选择性PET探针。如果体外敏感性和选择性是 已经达到的，第一阶段研究还将评估转基因AD小鼠体内探针的敏感性 模式。该程序的总体成功将提供一种无创的方法来检测和量化 体内AβO，并支持其作为监测疾病进展和的AD诊断工具的发展 治疗的影响和作为一种可以更好地理解AD病因的研究工具。