(-)-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、延缓或治疗阿尔茨海默病（AD）。五百万美国人 目前被诊断患有AD的人预计将在二十年内增加到1100 - 1600万， 有效的治疗。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， 特别反映了脑神经元和星形胶质细胞中存在的实时生化状态。这一进步将 允许研究者对AD神经病理学进行真实的时间评估，并有机会监测药物作用。 （-）-苯丝氨酸酒石酸盐是一种经证实的探针，能够影响AD神经病理学，这在AD神经病理学中被认为是重要的。 进展为痴呆，以及独立于AD病理学的潜在治疗方法， 在过去的30年里。来自临床前转基因AD模型和野生型AD的解剖学和生物化学证据 型小鼠和大鼠在创伤性脑损伤（TBI）和缺氧模型中的表达支持苯丝氨酸的翻译 保护神经元免于无法由苯丝氨酸的其他活性解释的前程序性细胞死亡（PPCD）。 我们已经开发了酒石酸苯丝氨酸的延长控释制剂，以确保成功 确定最大限度地保护神经元和预期预防痴呆的最佳剂量。 基于临床前发现、转化研究（TBI和AD试验）、临床开发 在NIA和FDA的评估下，我们建议进行一项1b期剂量递增临床试验， 每日给药，持续12周，以确定安全和耐受剂量，表征生物标志物反应，并 解释它们对细胞功能的重要性。本剂量-反应评价为推进 第二阶段的概念验证试验为实现这一目标，提出了两个具体目标： 外泌体生物标志物的性能，它们区分AD病理与未受损的能力，它们的 在老年人群中的重现性和精确度;目的2进行1b期剂量递增试验， 在AD早期出现苯丝氨酸。主要安全性目标是定义最大耐受剂量，并确定 治疗后出现的不良事件。生物标志物的目标是能够部署外来体测定 作为AD神经病理学的量度和苯丝氨酸对病理学的影响。 次要目的是：1）评估苯丝氨酸对认知的潜在短期影响; 2）告知 随后的2期外泌体生物标志物的概念验证试验，即，PPCD、突触分支等。 具有药物开发、认知障碍生物标志物、衰老 和阿尔茨海默病治疗的转化研究致力于该项目。结果将提供：1）一个 估计的安全、耐受良好的苯丝氨酸剂量; 2）外泌体生物标志物的参数估计;和3） 认知功效的参数估计推进到第2阶段。该提案符合NIA PAR的目标- 18-175，阿尔茨海默病和阿尔茨海默病相关的认知下降谱的试点临床试验。

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.