Novel extracorporeal device 'Amytrapper' to remove beta amyloid in Alzheimer's Disease.

摘要 阿尔茨海默病(AD)是老年痴呆症的最常见原因，患者患有 神经退行性疾病，影响全球约2500万人，被认为是第四大 常见的死因。持续观察到淀粉样蛋白β(Aβ)在大脑中的显著积聚 在公元后。由于它在AD中积累，从系统中去除有毒的Aβ有望使AD受益 病人。广泛的努力致力于开发针对Aβ及其受体的治疗干预 获得治疗AD的许可，但成效有限。使用抗Aβ持续修改靶向Aβ的尝试 产生Aβ的抗体或小分子抑制剂正在取得一些有利的成功。 尽管抗Aβ抗体达到了预期目标，但患者意外的免疫副作用 是一个令人担忧的问题。我们已经开发并鉴定了一种基于非免疫的逆转录病毒多肽， 具有显著Aβ结合特性的AMYTRAP-1。我们已经证明，Amytrap可以结合可溶性和 Aβ(Aβ40和Aβ42)难溶形式的体外实验及其可减小Aβ斑块大小和Aβ蛋白 在临床相关的阿尔茨海默病小鼠模型的大脑中的水平和恢复记忆功能。我们还有 结果表明，固定化AMYTRAP-1多肽可以结合和捕获血清样本中添加的Aβ。 浓度依赖方式。AMYTRAP-1多肽由于其D-氨基酸构型而稳定，并且它 是安全的，因为它在阿尔茨海默病小鼠中没有表现出任何免疫副作用。 在这一阶段中，我们建议开发一种体外系统，该系统可以选择性地从细胞中去除Aβ 在没有系统地引入患者的情况下进行循环。我们计划生成并测试一个 名为‘AmyTrapper’的原型体外柱可结合和去除血浆中的Aβ。目前在那里 没有治疗AD患者的体外系统。AmyTrapper是第一个治疗AD的同类药物。淀粉捕捉器 将以含有化学上连接到AMYTRAP-1肽的固体载体的盒的形式。我们 设想AmyTrapper将成为标准分离系统的一部分，其中AD患者的血浆是 通过选择性地隔离Aβ，不含β的血浆重新进入体内。减少了 循环性Aβ会使淀粉样蛋白平衡向外周移动，从而耗尽脑部Aβ 负担。在这项概念验证研究中，我们将开发和表征AmyRapper，并测试其 在血浆中加入Aβ42的性能。在目标1中，我们将合成并表征淀粉捕捉剂 Aβ结合效率；在目标2中，评估Amytrapper(混悬剂形式)对 在血浆和AIM 3中结合Aβ，为ITS准备和测试AmyTrapper原型(柱格式) A-β在血浆中的滞留能力我们有信心在这一努力中取得成功，因为我们已经设计了一个 有明确目标和可交付成果的适当目标产品计划。此外，我们已经安排了右翼 目前正在营销FDA批准的分离柱用于其他适应症的行业领导者 CRO将与我们合作。在研究的后续阶段，该设备将在临床上进行测试 相关的AD小鼠模型，随后是人类研究中的第一个。

Abstract Alzheimer’s disease (AD) is the most common cause of dementia among elderly patients afflicted by neurodegenerative diseases, affecting about 25 million people worldwide and regarded as the fourth most common cause of death. Significant accumulation in the brain of Amyloid β (Aβ) is consistently observed in AD. Due to its accumulation in AD, removal of the toxic Aβ from the system is expected to benefit AD patients. Extensive efforts were devoted to developing therapeutic interventions targeting Aβ and its clearance to treat AD but with limited success. Ongoing modified attempts to target Aβ using anti-Aβ antibodies or small molecule inhibitors of Aβ production are yielding somewhat favorable success. Although anti-Aβ antibodies meet the desired goal, unintended immunological side-effects in patients has been a concern. We have developed and characterized a non-immune based retro-inverso peptide, Amytrap-1 with significant Aβ binding properties. We have shown that Amytrap can bind both soluble and less soluble forms of Aβ (Aβ40 and Aβ42) in vitro and that it can reduce Aβ plaque size and Aβ protein levels in the brain of a clinically relevant mouse model of AD and restore memory functions. We have also shown that immobilized Amytrap-1 peptide can bind and trap spiked Aβ from sera samples in a concentration dependent manner. Amytrap-1 peptide is stable due to its D-amino acid configuration and it is safe as it did not show any immune side effects in the AD mice. In this phase 1, we propose to develop an ex-vivo system that could selectively remove Aβ from the circulation without being systemically introduced into the patients. We plan to generate and test a prototype extracorporeal column named ‘Amytrapper’ to bind and remove Aβ from plasma. Currently there are no extracorporeal systems to treat AD patients. Amytrapper is first of its kind to treat AD. Amytrapper will be in the form of a cartridge containing a solid support chemically linked to Amytrap-1 peptide. We envision Amytrapper to be a part of a standard apheresis system, wherein plasma from AD patients is passed through to selectively sequester Aβ, and Aβ-free plasma re-enters the body. Reducing the circulatory Aβ will shift the amyloid equilibrium towards the periphery and thus will deplete brain Aβ burden. In this proof-of-concept study, we will develop and characterize Amyrapper and test its performance with plasma spiked with Aβ42. We will, in Aim 1, synthesize and characterize Amytrapper for Aβ binding efficiency; in Aim 2, evaluate sensitivity and specificity of Amytrapper (suspension format) to bind Aβ in plasma and in Aim 3, prepare and test Amytrapper prototype (column format) for its sequestering ability of Aβ in plasma. We are confident to succeed in this effort as we have designed an appropriate target product plan with defined goals and deliverables. Besides, we have lined up the right industry leaders who are currently marketing FDA approved apheresis columns for other indications as CRO’s to collaborate with us. In subsequent phase of the study, the device will be tested in a clinically relevant mouse model of AD followed by a first in human study.