Designed Vehicles for Blood Brain Barrier Traversal

设计用于穿越血脑屏障的车辆

基本信息

批准号：
10200639
负责人：
DAVID BAKER
金额：
$ 51.78万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200639
关键词：
Affinity Alzheimer&apos s Disease Amines Antibodies Binding Binding Proteins Biodistribution Biological Assay Blood Blood - brain barrier anatomy Brain Cells Chemicals Clinical DNA biosynthesis Diffuse Directed Molecular Evolution Drug Delivery Systems Escherichia coli Feedback Future Gene Pool Goals Hydrogen Bonding Hydrophobicity In Vitro Knowledge Label Libraries Measures Mediating Mission Modeling Molecular Sieve Chromatography Monoclonal Antibodies Mus Neuraxis Neurodegenerative Disorders Neurologic Neurological outcome Nucleocapsid Nutrient Oncogenes Outcome Parkinson Disease Peptides Permeability Pharmaceutical Preparations Pharmacology Property Protein Engineering Proteins Public Health Radiolabeled Rodent Route Side Signal Transduction Specificity Stroke Structure Surface Synthetic Genes System TFRC gene Testing Therapeutic Therapeutic Clinical Trial Therapeutic Monoclonal Antibodies Toxic effect United States National Institutes of Health Variant Vertebral column X-Ray Crystallography Yeasts barrier to care base blood-brain barrier crossing blood-brain barrier penetration blood-brain barrier permeabilization brain cell chemical property design disability improved improved outcome in vivo innovation insight nervous system disorder novel drug class nucleic acid-based therapeutics passive transport receptor receptor binding screening success tool

项目摘要

PROJECT SUMMARY Emerging peptide-, protein-, and nucleic acid-based therapeutics for the treatment of Alzheimer’s disease and other neurologic conditions are blocked from diffusing into the brain by the blood–brain barrier (BBB). The long-term goal of this project is to deliver large therapeutic cargo such as these into the brain using designed BBB-crossing drug-delivery vehicles. The overall objectives are to (i) leverage recent breakthroughs in computational peptide design to yield new knowledge about BBB permeability and (ii) to designed from scratch new proteins that ferry cargo into the brain by exploiting natural systems that the brain uses to receive nutrients and signals. The central hypothesis is that the systematic design of functional biomolecules will yield new insights and tools for improving the delivery of large biomolecule therapeutics into the brain. The specific aims are: 1) to systematically and rationally discover the physiochemical properties which confer BBB permeability to designed peptide macrocycles (a promising new class of therapeutics); 2) to computationally design small, hyperstable proteins which bind to receptors that naturally cycle between the blood- and brain-side of the BBB; and 3) to fuse the binding proteins generated in Aim 2 to various drug-binding/packaging proteins, thereby creating protein assemblies that ferry large therapeutics into the brain. This project is innovative because it proposes to resolve a long-standing barrier to the treatment of neurologic diseases (namely, the difficulty of delivering therapeutics into the brain) by designing from scratch new BBB-crossing drug delivery vehicles. The project is significant because it is expected to provide tools which will improve outcomes in a range of future clinical trials of therapeutics which require delivery into the brain.

项目摘要新兴肽，蛋白质和基于核酸的疗法用于治疗阿尔茨海默氏病和其他神经系统条件被血脑屏障（BBB）阻塞到大脑中的扩散。该项目的长期目标是使用设计 BBB交叉药车。总体目标是（i）利用最近的突破计算肽设计，以产生有关BBB渗透性的新知识和（ii）从头开始设计的通过利用大脑用于接受营养的天然系统，将货物运送到大脑中的新蛋白质和信号。中心假设是功能生物分子的系统设计将产生新的洞察力和工具，用于改善大型生物分子疗法向大脑的递送。具体目标是：1）系统和理性地发现会议的生理化学特性设计肽大环（一种有希望的新疗法）； 2）到计算设计小，催眠蛋白与BBB血液和大脑之间自然循环的受体结合； 3）将AIM 2中产生的结合蛋白融合到各种药物结合/包装蛋白中，从而融合创建蛋白质组件，将大型疗法渡轮到大脑中。这个项目是创新的，因为它解决神经疾病治疗的长期障碍的提议（即困难通过从头开始设计新的BBB跨药物递送车，将疗法递送到大脑中）。项目很重要，因为预计将提供工具，以改善未来的结果需要输送大脑的治疗的临床试验。