Novel Extracorporeal Device 'Amytrapper' To Remove Beta Amyloid In Alzheimer'sDisease

新型体外装置“Amytrapper”可去除阿尔茨海默病中的β淀粉样蛋白

基本信息

批准号：
10818780
负责人：
PAZHANI SUNDARAM
金额：
$ 80.67万
依托单位：
RECOMBINANT TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10818780
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-42 Amyloid beta-Protein Animals Antibodies Award Behavioral Binding Biotechnology Biotinylation Blood Blood Component Removal Blood specimen Brain Breakthrough device Canis familiaris Capital Catheters Cause of Death Characteristics Chicago Circulation Classification Clinical Cognition Cognitive Complement Connecticut Coupled Dementia Devices Dialysis procedure Disease Equilibrium Equipment Evaluation Excision FDA approved Feedback Funding Generations Goals Hemodialysis Human Immunologics In Vitro Incidence Injections Investments Kidney Failure Knowledge Legal patent Liquid substance Market Research Marketing Medical Medical Device Memory Modeling Monoclonal Antibodies Mus Names Patients Peptide Initiation Factors Peptides Persons Pharmaceutical Preparations Phase Physiological Pilot Projects Plasma Play Privatization Rattus Recombinants Regimen Regulation Reporting Research Retro-Inverso Peptide Role Safety Saline Sampling Small Business Innovation Research Grant Technology Testing Tg2576 Therapeutic Time Toxicology Urea Whole Blood Work abeta accumulation clinically relevant commercialization design ethylene glycol experience extracellular first-in-human human study improved in vivo in vivo evaluation innovation mouse model novel pharmacologic pre-clinical prevent programs prototype research and development scale up side effect skills success timeline treatment strategy

项目摘要

Abstract Alzheimer’s disease is the most common cause of dementia and fourth most common cause of death. Amyloid-beta (Aβ) plays a crucial role in initiation and progression of Alzheimer’s disease (AD). Removal of circulating Aβ would shift the equilibrium in Aβ levels between brain and blood towards blood. This shift would deplete brain amyloid levels and improve memory. Three commercial monoclonal antibodies Adecanumab (Biogen), Lacenumab (Eisai) and Donanemab (Eli Lilly) have been approved by the FDA after showing cognitive improvement by reducing amyloid. Recombinant Technologies [RT] has developed an extracorporeal apheresis device, namely, Amytrapper Catheter to sequester blood Aβ. The device is built on our IP-protected active pharmacological ingredient [API], a tetrameric retro-inverso (RI) peptide, named Amytrap peptide. The device is a medically viable catheter which is coated inside with the API. Amytrap peptide prevents Aβ self-aggregation by binding to a specific motif on Aβ that promotes its misfolding and self-aggregation. Amytrap peptide has been shown to bind both soluble and insoluble forms of amyloid efficiently with little side effects. The API is superior in that it is a small peptide, not an antibody and it does not trigger any immunological side effects. Previous research through SBIR phases I and II met or exceeded the intended goals. We completed the following quantitative milestones: 1) we obtained proof of concept for a prototype Amytrapper Catheter device in vitro. It bound and retained biotinylated Aβ42 (spiked) in a concentration dependent manner from circulating fluids including sera or plasma from mice, rat and humans, in vitro. 2) we have obtained in vivo proof of concept for the device in AD model rats. Blood amyloid reduction coupled with behavioral improvement was observed in these rats after catheter-apheresis. 3) we have obtained preliminary proof of concept with the device to remove native amyloid from blood samples of a small number of patients with AD. 4) Completed market research for the device by partnering with Bio Heath Innovations (MD) with the help of an NIA-sponsored TABA program which produced encouraging feedback from key opinion leaders including end users 5) We have raised outside funds through partnership with Start Engine Capital LLC via Regulation CF and we plan to continue this effort. This phase IIB proposal is a necessary and logical extension of our ongoing research and commercialization efforts that will bring the device from bench to the patient. We plan to improvise and optimize the Amytrapper catheter device. Reflecting on these goals, in this proposal, we plan: in aim 1. Scaled up synthesis (GLP grade), optimization and characterization of API, in aim 2. Fine-tune and improvise Amytrapper Catheter device utilizing amyloid-spiked human blood samples, in aim 3. Confirm preclinical POC on the streamlined catheter device by testing Amytrapper Catheter on blood samples from AD patients and in aim 4. Complete regulatory filing and FDA clearance for Amytrapper Catheter. We have partnered with Connecticut Innovations Inc, a local biotech venture investment firm and SA Capital Partners NY, to raise additional private funds. This phase 2B award is likely to attract a syndicate of investors to help us succeed in our commercialization efforts. At the end of this study, we would have completed an IDE (investigational new device exemption) with the FDA for an eventual first in human [FIH] study. We present well defined goals with realistic milestones and deliverables that is supported by established players and partners. We believe that removal of amyloid by this device in AD patients will significantly improve their living conditions and complement existing therapeutic regimen.

抽象的阿尔茨海默病是痴呆症的最常见原因，也是第四大常见死因。 β 淀粉样蛋白 (Aβ) 在阿尔茨海默病 (AD) 的发生和进展中发挥着至关重要的作用。循环 Aβ 的去除将使大脑和血液之间 Aβ 水平的平衡向这种转变会消耗大脑中的淀粉样蛋白水平并改善记忆力。抗体 Adecanumab (Biogen)、Lacenumab (Eisai) 和 Donanemab (Eli Lilly) 已获得批准 FDA 在通过减少淀粉样蛋白显示出认知改善后。开发了一种体外单采装置，即 Amytrapper 导管，用于隔离血液 Aβ。设备基于我们受 IP 保护的活性药理成分 [API]，一种四聚体逆向逆 (RI)肽，命名为Amytrap肽，该装置是一种医学上可行的导管，内部有涂层。 Amytrap 肽通过与 Aβ 上的特定基序结合来防止 Aβ 自聚集。 Amytrap 肽可促进其错误折叠和自我聚集。该 API 的优点在于其体积小，可以有效地产生不溶性形式的淀粉样蛋白，且副作用很小。肽，不是抗体，不会引发任何免疫副作用。之前通过 SBIR 第一阶段和第二阶段的研究达到或超过了预期目标。以下定量里程碑：1) 我们获得了 Amytrapper 导管原型的概念验证它以浓度依赖性方式结合并保留生物素化的 Aβ42（加标）。我们在体外从小鼠、大鼠和人类的循环液（包括血清或血浆）中获得了这种物质。该装置在 AD 模型大鼠中的体内概念验证与血液淀粉样蛋白减少相结合。导管分离术后观察到这些大鼠的行为改善3）我们已经获得。初步证明该装置可从一小部分人的血液样本中去除天然淀粉样蛋白 4) 与 Bio Heath 合作完成了该设备的市场研究。在 NIA 赞助的 TABA 计划的帮助下进行创新 (MD)，该计划产生了令人鼓舞的成果包括最终用户在内的关键意见领袖的反馈 5) 我们通过以下方式筹集了外部资金通过 CF 法规与 Start Engine Capital LLC 建立合作伙伴关系，我们计划继续这一努力。 IIB 期提案是我们正在进行的研究和商业化的必要且合乎逻辑的延伸我们计划临时改进并优化该设备。考虑到这些目标，在本提案中，我们计划：目标 1. 扩大规模目标 2 中 API 的合成（GLP 级）、优化和表征。微调和即兴创作 Amytrapper 导管装置利用掺有淀粉样蛋白的人体血液样本，目标 3：确认临床前通过使用来自 AD 的血液样本测试 Amytrapper 导管，对简化的导管装置进行 POC 目标 4. 完成 Amytrapper 导管的监管备案和 FDA 批准。与当地生物技术风险投资公司 Connecticut Innovations Inc 和 SA Capital 合作纽约合作伙伴，筹集额外的私人资金该 2B 阶段的奖项可能会吸引一群财团。在本研究结束时，我们将获得投资者的帮助，帮助我们取得商业化的成功。与 FDA 完成了 IDE（研究性新设备豁免），最终成为人类首次 [FIH] 研究提出了明确的目标以及现实的里程碑和可交付成果，并得到了支持。我们相信，通过该设备去除 AD 患者中的淀粉样蛋白将有效。显着改善他们的生活条件并补充现有的治疗方案。