(-)-Phenserine inhibition of neuronal death in Alzheimer's disease and developing brain-labeled plasma exosomes assays as biomarkers for a phenserine phase 1b ascending dose trial

(-)-Phenserine 抑制阿尔茨海默病中的神经元死亡，并开发脑标记血浆外泌体检测作为 phenserine 1b 期剂量递增试验的生物标志物

• 批准号: 9924479
• 负责人: Clive Ballard
• 金额: $ 70.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924479
• 关键词: Address; Adverse event; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; American; Anatomy; Animals; Anoxia; Apoptosis; Astrocytes; Autophagocytosis; BAX gene; BCL2 gene; Biochemical; Biologic Development; Biological Assay; Biological Markers; Brain; CASP3 gene; Cell Death; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cohort Studies; Collaborations; Companions; Dementia; Development; Diagnosis; Disease; Disease Marker; Dose; Drug Kinetics; Drug Monitoring; Evaluation; Formulation; Foundations; Functional disorder; Future; Genes; Goals; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Intervention; Label; Legal patent; Maintenance; Maximum Tolerated Dose; Measures; Modeling; Modification; Molecular; Nerve Degeneration; Neuronal Dysfunction; Neuronal Injury; Neurons; Older Population; Oral; Outcome; Participant; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Placebos; Plasma; Pre-Clinical Model; Preparation; Prevention; Process; Process Measure; Proteins; Randomized; Rattus; Reproducibility; Research Personnel; Role; Safety; Sampling; Source; Synapses; Synapsins; Synaptophysin; TP53 gene; Tablets; Tartrates; Testing; Therapeutic; Time; Translational Research; Translations; Traumatic Brain Injury; Wild Type Mouse; base; clinical development; clinically relevant; clinically translatable; cohort; controlled release; cytokine; drug development; effective therapy; efficacy evaluation; exosome; improved; inhibitor/antagonist; interest; multidisciplinary; neurogranin; neuroinflammation; neuron loss; neuropathology; novel; phenserine; pre-clinical; predicting response; preservation; prevent; protein expression; response; response biomarker; sound; synaptopodin; synaptotagmin II; tablet formulation; tool; transgenic model of alzheimer disease

There are no effective drugs to prevent, delay or treat Alzheimer’s disease (AD). The 5 million Americans currently diagnosed with AD is projected to increase to 11-16 million within two decades in the absence of effective therapies. We propose to develop for use in humans, plasma based exosome biomarker assays specifically reflecting the real-time biochemical state present in brain neurons and astrocytes. This advance will allow investigators real time assessments of AD neuropathology and opportunities to monitor drug effects. (-)-Phenserine tartrate is both a proven probe able to affect AD neuropathology that is considered important in progression to dementia, and a potential therapeutic operating independently from the AD pathology targeted over the last 30 years. Anatomical and biochemical evidence from preclinical transgenic AD models and wild type mice and rats in traumatic brain injury (TBI) and anoxia models support the translation of phenserine protection of neurons from preprogrammed cell death (PPCD) unexplained by other activities of phenserine. We have developed an extended controlled release formulation of phenserine tartrate to insure successful determination of optimal dosing that maximizes preservation of neurons and expected prevention of dementia. Based on a foundation of preclinical discovery, translational research (TBI and AD trials), clinical development at NIA, and FDA assessment, we propose a phase 1b ascending dose clinical trial of four phenserine doses given daily for 12 weeks to establish a safe and tolerated dose, to characterize biomarker responses, and to interpret their significance for cellular functioning. This dose-response evaluation prepares for advancement to a phase 2 proof of concept trial. Two specific aims are proposed to achieve this goal: Aim 1 to assess the performance of the exosome biomarkers, their ability to distinguish AD pathology from not impaired, their reproducibility, and precision in older populations; Aim 2 to conduct a phase 1b ascending dose trial of phenserine in early AD. Primary safety objectives are to define a maximally tolerated dose, and determine treatment emergent adverse events. Biomarker objectives are to enable the deployment of exosomes assays as measures of AD neuropathology and phenserine’s effects on pathology. Secondary objectives are to: 1) assess potential short-term effects of phenserine on cognition; 2) inform an ensuing phase 2 proof of concept trial with exosome biomarkers, i.e., PPCD, synaptic arborization, etc. A multi- disciplinary investigator team with expertise in drug development, biomarkers of cognitive impairment, aging, and translational research for Alzheimer therapeutics is committed to the project. Outcomes will provide: 1) an estimated safe, well-tolerated phenserine dose; 2) parameter estimates for the exosome biomarkers; and 3) parameter estimates for cognitive efficacy to advance to phase 2. The proposal meets objectives of NIA PAR- 18-175, Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.

没有有效的药物可以预防、延缓或治疗 500 万美国人。 如果不采取措施，目前被诊断患有 AD 的人数预计将在二十年内增加到 11-1600 万人。 我们建议开发用于人类的基于血浆的外泌体生物标志物测定。 具体反映大脑神经元和星形胶质细胞中存在的实时生化状态。 允许研究人员实时评估 AD 神经病理学并有机会监测药物效果。 (-)-Phenserine 酒石酸盐是一种经过验证的探针，能够影响 AD 神经病理学，这在 AD 神经病理学中被认为很重要 痴呆症，以及独立于 AD 病理学的潜在治疗操作进展 过去 30 年来自临床前转基因 AD 模型和野生动物的解剖学和生化证据。 创伤性脑损伤（TBI）和缺氧模型中的小鼠和大鼠模型支持苯酚的翻译 保护神经元免受预编程细胞死亡（PPCD）的影响，这是苯酚酚的其他活性无法解释的。 我们开发了酒石酸苯酚缓释制剂，以确保成功 确定最佳剂量，最大限度地保护神经元并预期预防痴呆。 基于临床前发现、转化研究（TBI 和 AD 试验）、临床开发的基础 在 NIA 和 FDA 评估中，我们提议进行四种苯酚剂量的 1b 期递增剂量临床试验 每日给药，持续 12 周，以确定安全且耐受的剂量，表征生物标志物反应，并 解释它们对细胞功能的重要性。这种剂量反应评估为进一步发展做好准备。 为实现这一目标，提出了第二阶段的概念验证试验：目标 1 评估 外泌体生物标志物的性能、区分 AD 病理学与未受损的能力、 老年人群中的重现性和精确度；目标 2 进行 1b 期剂量递增试验 早期 AD 中苯酚的主要安全目标是确定最大耐受剂量并确定。 治疗突发不良事件的生物标志物目标是能够部署外泌体检测。 作为 AD 神经病理学和苯酚对病理学影响的测量。 次要目标是：1）评估苯酚对认知的潜在短期影响；2）告知 随后使用外泌体生物标志物进行第二阶段概念验证试验，即 PPCD、突触树枝化等。 学科研究者团队在药物开发、认知障碍生物标志物、衰老、 该项目致力于阿尔茨海默病疗法的转化研究，结果将提供：1） 估计的安全、耐受性良好的苯酚剂量；2) 外泌体生物标志物的参数估计； 认知功效的参数估计将进入第 2 阶段。该提案符合 NIA PAR- 的目标 18-175，阿尔茨海默氏病和年龄相关认知能力下降的试点临床试验。