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

新型体外装置“Amytrapper”可去除阿尔茨海默病中的β淀粉样蛋白。

• 批准号: 9410435
• 负责人: PAZHANI SUNDARAM
• 金额: $ 14.85万
• 依托单位: RECOMBINANT TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9410435
• 关键词: Abeta synthesis; Address; Adverse effects; Affect; Affinity; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid beta-Protein; Antibodies; Back; Binding; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Component Removal; Brain; Cause of Death; Chemicals; Clinic; Collaborations; Coupled; Data; Dementia; Devices; Dextrans; Equilibrium; Excision; FDA approved; Frequencies; Future; Goals; Human; Immobilization; Immune; Immunologics; In Vitro; Industry; Link; Marketing; Memory; Modality; Modeling; Mus; Names; Neurodegenerative Disorders; Patients; Peptides; Performance; Peripheral; Pharmacology; Phase; Plasma; Prevention; Procedures; Property; Rest; Retro-Inverso Peptide; Rodent; Sampling; Senile Plaques; Sensitivity and Specificity; Solid; Specificity; Standardization; Suspensions; System; Testing; Therapeutic; Therapeutic Intervention; Time; abeta accumulation; base; beta-site APP cleaving enzyme 1; clinically relevant; design; experience; human study; inhibitor/antagonist; innovation; mouse model; neuron loss; novel; older patient; prevent; prototype; receptor; receptor function; small molecule inhibitor; success

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.

摘要 阿尔茨海默氏病（AD）是患有阿尔茨海默病的老年患者中痴呆症的最常见原因。 神经退行性疾病，影响全球约2500万人，被认为是第四大 常见死因始终观察到β淀粉样蛋白（Aβ）在脑中的显著蓄积 在AD中。由于其在AD中的蓄积，预期从系统中去除毒性Aβ对AD有益 患者广泛的努力致力于开发针对Aβ及其受体的治疗干预措施。 但治疗效果有限。正在进行的使用抗A β靶向Aβ的改良尝试 抗体或Aβ产生的小分子抑制剂正在产生某种有利的成功。 虽然抗A β抗体达到了预期的目标，但患者的非预期免疫副作用仍然存在。 是个问题我们已经开发并表征了一种基于非免疫的反转肽， Amytrap-1具有显着的Aβ结合特性。我们已经证明Amytrap可以结合可溶性和 在体外，它可以减少Aβ斑块大小和Aβ蛋白， 在临床相关的AD小鼠模型的脑中的水平和恢复记忆功能。我们还 结果显示，固定化Amytrap-1肽可以结合并捕获血清样品中掺入的Aβ， 浓度依赖方式。Amytrap-1肽由于其D-氨基酸构型而稳定， 是安全的，因为它在AD小鼠中没有显示出任何免疫副作用。 在第一阶段，我们计划开发一种离体系统，可以选择性地去除Aβ， 循环，而不会全身性地引入患者体内。我们计划生成并测试一个 名为“Amytrapper”的原型体外柱结合并从血浆中去除Aβ。当前 没有体外系统来治疗AD患者。Amytrapper是第一个治疗AD的药物。阿米特拉普 将是含有与Amytrap-1肽化学连接的固体支持物的药筒形式。我们 设想Amytraper是标准单采系统的一部分，其中来自AD患者的血浆被 选择性地隔离Aβ，无Aβ的血浆重新进入体内。减少 循环Aβ将使淀粉样蛋白平衡向外周移动，从而消耗脑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 使用加标Aβ42的血浆进行性能分析。我们将在目标1中合成和表征Amytraper， Aβ结合效率;在目的2中，评价Amytraper（混悬液形式）对以下指标的灵敏度和特异性： 结合血浆和目标3中的Aβ，制备并检测Amytraper原型（柱格式）的 血浆中Aβ的螯合能力。我们有信心在这方面取得成功，因为我们已经设计了一个 具有明确目标和可交付成果的适当目标产品计划。此外，我们还安排了 目前正在销售FDA批准的用于其他适应症的单采柱的行业领导者， 合同研究组织与我们合作。在研究的后续阶段，将在临床试验中对器械进行测试。 AD的相关小鼠模型，随后是首次人体研究。