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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.

摘要阿尔茨海默病是痴呆症最常见的原因，也是第四大常见的死亡原因。 β-淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的发生和发展中起着重要作用。清除循环中的Aβ将使脑和血液之间的Aβ水平平衡向血这种转变将消耗大脑淀粉样蛋白水平并改善记忆力。三种商业单克隆抗体抗体Adecanumab（Biogen）、Lacenumab（Eli Lilly）和Donanemab（Eli Lilly）已被批准用于治疗癌症。在通过减少淀粉样蛋白而显示出认知改善后，FDA。Recombinant Technologies（RT）开发了一种体外单采装置，即Amytrapper导管，用于隔离血液Aβ。的该设备是建立在我们的知识产权保护的活性药理学成分[API]，一个四聚体的逆向转化， (RI)肽，命名为Amytrap肽。该器械是一种医用导管，内部有涂层使用API。Amytrap肽通过与Aβ上的特定基序结合来防止Aβ自聚集，促进其错误折叠和自我聚集。Amytrap肽已经显示结合可溶性和可溶性的蛋白质。不溶性形式的淀粉样蛋白，有效地与小的副作用。API的上级之处在于它是一个小的肽，而不是抗体，它不会引发任何免疫副作用。通过SBIR第一和第二阶段以前的研究达到或超过了预期的目标。我们完成了以下定量里程碑：1）我们获得了原型Amytrapper导管的概念证明体外器械。其以浓度依赖性方式结合并保留生物素化Aβ42（加标）来自循环流体，包括来自小鼠、大鼠和人的血清或血浆。2)我们所获得在AD模型大鼠中对器械进行体内概念验证。血淀粉样蛋白减少加上在这些大鼠中观察到导管单采术后的行为改善。3)我们所获得初步的概念证明与设备，以消除天然淀粉样蛋白的血液样本的小 AD患者的数量。4)通过与Bio Heath合作完成器械的市场研究创新（医学博士）的帮助下，国家情报局赞助的TABA计划，产生了令人鼓舞的包括最终用户在内的主要意见领袖的反馈5）我们通过以下方式筹集了外部资金：我们将通过Regulation CF与Start Engine Capital LLC建立合作伙伴关系，并计划继续这一努力。这 IIB阶段的建议是我们正在进行的研究和商业化的必要和合乎逻辑的延伸将器械从实验室带到患者身上的努力。我们计划即兴发挥并优化 Amytrapper导管器械。考虑到这些目标，在本提案中，我们计划：扩大目标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，利用淀粉样蛋白掺入的人血液样品，在目标3中。确认临床前通过在AD血样上测试Amytrapper导管，对流线型导管器械进行POC 患者和目标4。完成Amytrapper导管的监管备案和FDA批准。我们有与当地生物技术风险投资公司Connecticut Innovations Inc和SA Capital合作合作伙伴纽约，以筹集更多的私人资金。这个2B阶段的奖励可能会吸引一个财团，投资者帮助我们在商业化方面取得成功。在这项研究的最后，我们将有完成了与FDA的IDE（研究性新器械豁免），最终首次用于人体 [FIH]study.我们提出了明确的目标与现实的里程碑和可交付成果，这是支持已建立的参与者和合作伙伴。我们相信，在AD患者中通过这种装置去除淀粉样蛋白将显著改善其生活条件并补充现有治疗方案。