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.

抽象的 阿尔茨海默氏病 (AD) 是老年患者痴呆的最常见原因 神经退行性疾病，影响全球约 2500 万人，被视为第四大疾病 β淀粉样蛋白（Aβ）在大脑中大量积聚是常见的死亡原因。 由于其在 AD 中的积累，从系统中去除有毒的 Aβ 预计将有利于 AD。 人们致力于开发针对 Aβ 及其的治疗干预措施。 已获得治疗 AD 的许可，但目前正在尝试使用抗 Aβ 药物来靶向 Aβ，但成效有限。 Aβ 产生的抗体或小分子抑制剂正在取得一定的成功。 尽管抗 Aβ 抗体达到了预期目标，但患者体内出现了意想不到的免疫副作用 我们已经开发并表征了一种基于非免疫的逆反肽， Amytrap-1 具有显着的 Aβ 结合特性 我们已经证明 Amytrap 可以结合可溶性和可溶性 Aβ。 体外不易溶解的 Aβ（Aβ40 和 Aβ42）形式，并且可以减少 Aβ 斑块大小和 Aβ 蛋白 我们还发现，在临床相关的 AD 小鼠模型中，其大脑中的水平可以恢复记忆功能。 研究表明，固定化的 Amytrap-1 肽可以结合并捕获血清样本中的尖峰 Aβ。 Amytrap-1 肽由于其 D-氨基酸构型而稳定，并且它 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，我们建议开发一种离体系统，可以选择性地从细胞中去除 Aβ。 我们计划生成并测试一种循环系统，而不将其系统地引入患者体内。 原型体外柱名为“Amytrapper”，用于结合并去除血浆中的 Aβ。 没有治疗 AD 患者的体外系统 Amytrapper 是第一个治疗 AD 的系统。 将采用包含与 Amytrap-1 肽 We 化学连接的固体支持物的盒的形式。 Amytrapper 设想成为标准单采血液分离系统的一部分，但是来自 AD 患者的血浆 通过选择性地隔离 Aβ，并且不含 Aβ 的血浆重新进入体内。 循环 Aβ 将使淀粉样蛋白平衡向外周移动，从而耗尽大脑 Aβ 在这项概念验证研究中，我们将开发 Amyrapper 并对其进行表征并测试其。 在目标 1 中，我们将合成并表征 Amytrapper 的性能。 Aβ 结合效率；在目标 2 中，评估 Amytrapper（悬浮液形式）的敏感性和特异性 结合血浆中的 Aβ，并在目标 3 中，制备并测试 Amytrapper 原型（柱格式）的 我们有信心在这项工作中取得成功，因为我们设计了一种 具有明确目标和可交付成果的适当目标产品计划此外，我们还准备了正确的产品计划。 目前正在营销 FDA 批准的用于其他适应症的单采血液分离柱的行业领导者，例如 CRO 与我们合作，在研究的后续阶段，该设备将进行临床测试。 相关的 AD 小鼠模型随后在人类研究中首次出现。