A blood-brain-barrier permeable imaging biomarker for microtubules in the brain: A first-in-human clinical trial

大脑微管的血脑屏障可渗透成像生物标志物：首次人体临床试验

• 批准号: 10193563
• 负责人: Joseph John Mann
• 金额: $ 33.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193563
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Axon; Axonal Transport; Binding; Biological Markers; Blood specimen; Brain; Brain Diseases; Brain imaging; Brain region; Cause of Death; Cell division; Cell physiology; Central Nervous System Diseases; Clinic; Clinical Trials; Computer software; Cyclic GMP; Cytoplasmic Granules; Data; Development; Disease; Eukaryotic Cell; Evaluation; Functional disorder; Goals; Grant; Health; Human; Image; In Vitro; Injections; Institutional Review Boards; Intracellular Transport; Kinetics; Letters; Mental disorders; Methods; Microtubule Depolymerization; Microtubule-Associated Proteins; Microtubules; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neuronal Plasticity; Neurons; Organ; Organelles; Parkinson Disease; Patients; Play; Positioning Attribute; Positron-Emission Tomography; Process; Proteins; Public Health; RNA; Radiation exposure; Radiolabeled; Reporting; Reproducibility; Research; Research Proposals; Rodent; Role; Senile Plaques; Skeleton; Structural Protein; Structure; Testing; Time; Tracer; Translating; Tubulin; United States; Wild Type Mouse; Work; X-Ray Computed Tomography; addiction; base; bench to bedside; beta Tubulin; blood-brain barrier penetration; blood-brain barrier permeabilization; cell motility; design; dosimetry; experience; extracellular; first-in-human; hyperphosphorylated tau; imaging agent; imaging biomarker; in vivo; interest; kinetic model; mouse model; nervous system disorder; new therapeutic target; non-invasive imaging; nonhuman primate; novel; pre-clinical; preclinical study; radiotracer; success; targeted treatment; tool; uptake

Application Number: 1 R21 AG072570-01 Contact PD/PI: Mintz, Akiva A blood-brain-barrier permeable imaging biomarker for microtubules in Alzheimer’s Disease: A first-in-human evaluation. Tools to study microtubule dysfunction could have a transformative impact on neurodegenerative diseases including Alzheimer's disease (AD), the sixth-leading cause of death in the United States, which afflicted 5.5 million Americans in 2017. AD is characterized by extracellular amyloid plaques composed of Aβ fragments and intracellular neurofibrillary tangles formed by hyperphosphorylated tau, a protein that normally functions as a microtubule‐associated protein (MAP). In AD, it has been reported that microtubule dynamics are affected early in the disease process, including disturbed microtubule assembly by sequestration of MAPs and microtubule depolymerization induced by Aβ plaques. The microtubule skeleton is critical for neuronal health by providing the main tracks for axonal transport, contributing to structural integrity, and playing a significant role in neuronal plasticity and cell division. Thus, abnormalities in microtubule dynamics are thought to play a major role in the neurodegeneration seen in AD. The goal of this R21 is to develop a BBB-penetrant PET radiotracer that can image and quantify microtubules in real-time, leveraging our preliminary data and expertise in positron emission tomography (PET). This novel radiotracer can elucidate the role of microtubules in AD and aid in the development and evaluation of novel microtubule-targeted therapeutic strategies. The central hypothesis is that [11C]MPC-6827, our novel tubulin PET tracer, can cross the BBB and non-invasively image and quantify microtubule dynamics to visualize early alterations in AD and changes over time in patients afflicted with AD. Our hypothesis is based on our preliminary data showing that MPC- 6827 binds β-tubulin in vitro, can be radiolabeled, crosses the BBB in non-human primates, and demonstrates lower binding in mouse models of AD. The FDA has granted us a “safe to proceed” letter for our exploratory first-in-human IND to image with [11C]MPC-6827. We will pursue two specific aims that will enable us to test our novel tracer in AD patients. In Specific Aim 1, we will characterize the initial [11C]MPC-6827 dosimetry, as required by the FDA, by performing sequential first-in-human whole body PET/CT imaging on 5 subjects. In Aim 2, we will characterize [11C]MPC-6827 brain uptake and binding in a test-retest design, and develop quantification methods for PET [11C]MPC-6827 kinetics in the brain. Our criteria for success are that, at the conclusion of the proposed research, we will have validated [11C]MPC-6827 penetration of the BBB in humans, developed robust quantitative methods to analyze [11C]MPC- 6827 PET, and established the human dosimetry of our novel microtubule imaging agent with potential to image microtubule dynamics in AD. This will enable us to image microtubule dynamics in AD patients longitudinally and for the first time elucidate the role that microtubules play in the disease process, opening the door for novel therapeutics that target microtubules. We are well positioned to pursue the studies proposed here because of our direct experience performing first- in-human clinical trials and developing [11C]MPC-6827 from bench-to-bedside.

申请编号：1 R21 AG072570-01联系PD/PI：Akiva明茨 阿尔茨海默病微管的血脑屏障渗透性成像生物标记物：人类首次评估。 研究微管功能障碍的工具可能会对包括阿尔茨海默病(AD)在内的神经退行性疾病产生革命性影响。阿尔茨海默病是美国第六大死亡原因，2017年困扰着550万美国人。AD的特征是由Aβ片段组成的细胞外淀粉样斑块和由过度磷酸化的tau形成的细胞内神经纤维缠结，tau是一种正常功能的微管相关蛋白(MAP)。在AD中，已有报道在疾病过程的早期影响微管动力学，包括MAP的隔离导致的微管组装障碍和Aβ斑块引起的微管解聚。微管骨架对神经元的健康至关重要，它为轴突运输提供主要的轨迹，有助于结构的完整性，并在神经元的可塑性和细胞分裂中发挥重要作用。因此，微管动力学异常被认为在阿尔茨海默病的神经退行性变中起主要作用。R21的目标是利用我们在正电子发射断层扫描(PET)方面的初步数据和专业知识，开发一种可穿透血脑屏障的PET放射性示踪剂，可以实时成像和量化微管。这种新型的放射性示踪剂可以阐明微管在AD中的作用，并有助于开发和评估新的微管靶向治疗策略。中心假设是，我们的新型微管蛋白PET示踪剂[11C]MPC-6827可以跨越血脑屏障和非侵入性图像，并量化微管动力学，以可视化AD患者的早期变化和随时间的变化。我们的假设是基于我们的初步数据，该数据表明，MPC-6827在体外与β-微管蛋白结合，可以被放射性标记，在非人类灵长类动物中跨越血脑屏障，并在AD小鼠模型中表现出较低的结合。FDA已经批准了我们的探索性首例人类IND与[11C]MPC-6827进行成像的“安全继续进行”的信函。我们将追求两个具体目标，使我们能够在AD患者中测试我们的新型示踪剂。在具体目标1中，我们将按照FDA的要求，通过对5名受试者进行连续的人体全身PET/CT成像来表征初始的[11C]MPC-6827剂量学。在目标2中，我们将在测试-重测设计中表征[11C]MPC-6827脑摄取和结合的特征，并开发PET[11C]MPC-6827在脑中的动力学定量方法。我们成功的标准是，在拟议的研究结束时，我们将验证[11C]MPC-6827在人体内的血脑屏障穿透性，开发出稳健的定量方法来分析[11C]MPC-6827PET，并建立我们的新型微管显像剂的人体剂量学，具有潜在的AD微管动力学成像的潜力。这将使我们能够纵向成像AD患者的微管动力学，并首次阐明微管在疾病过程中所起的作用，为靶向微管的新疗法打开大门。我们处于有利的地位，可以继续进行这里提出的研究，因为我们有直接的经验，执行第一次人类临床试验和开发[11C]MPC-6827从工作台到床边。