(-)-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

目前还没有有效的药物来预防、推迟或治疗阿尔茨海默病(AD)。500万美国人 目前诊断为AD的人数预计将在20年内增加到1,100-1,600万人 有效的治疗方法。我们建议开发用于人类的、基于血浆的外切体生物标志物分析。 具体反映了脑神经元和星形胶质细胞中存在的实时生化状态。这一进展将 使调查人员能够实时评估AD的神经病理，并有机会监测药物影响。 (-)-酒石酸苯丝氨酸既是一种已被证明能够影响AD神经病理的探针，后者被认为在 进展为痴呆症，以及一种独立于AD靶向病理的潜在治疗操作 在过去的30年里。临床前转基因AD模型和野生型AD模型的解剖学和生化证据 创伤性脑损伤和缺氧模型中的典型小鼠和大鼠支持苯丝氨酸的翻译 保护神经元免受预编程细胞死亡(PPCD)的影响，但苯丝氨酸的其他活性无法解释。 我们已经开发了酒石酸非丝氨酸的缓释制剂，以确保成功 确定最佳剂量，以最大限度地保存神经元并预期预防痴呆症。 基于临床前发现、转化性研究(TBI和AD试验)、临床开发 在nia和fda的评估中，我们建议进行一项1b期递增剂量临床试验，共四种非丝氨酸剂量。 每日给药12周，以确定安全和耐受的剂量，表征生物标记物的反应，并 解释它们对细胞功能的意义。这一剂量-反应评估为进一步发展到 第二阶段概念验证试验。为实现这一目标提出了两个具体目标：目标1评估 外体生物标记物的表现，它们区分AD病理和非受损的能力，它们的 在老年人群中的重复性和精确度；目标2进行1b期剂量递增试验 公元早期的苯丝氨酸。主要的安全目标是定义最大耐受剂量，并确定 治疗突发不良事件。生物标记物的目标是能够部署外切体分析 作为阿尔茨海默病的神经病理学指标和非丝氨酸对病理的影响。 次要目标是：1)评估非丝氨酸对认知的潜在短期影响；2)告知 随后进行第二阶段概念验证试验，使用外体生物标记物，即PPCD、突触树枝等。 具有药物开发、认知障碍生物标记物、衰老、 阿尔茨海默病疗法的翻译研究致力于该项目。结果将提供：1) 估计的安全、耐受性良好的非丝氨酸剂量；2)外切体生物标志物的参数估计；以及3) 认知效能的参数估计将进入第二阶段。该提案符合NIA PAR- 18-175，阿尔茨海默氏症谱系和年龄相关认知下降的试点临床试验。

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.