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：
10614470
负责人：
DAVID BAKER
金额：
$ 49.55万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614470
关键词：
Affinity Alzheimer&apos s Disease Amines Antibodies Binding Binding Proteins Biodistribution Biological Assay Blood Blood - brain barrier anatomy Brain Cells Central Nervous System Clinical Clinical Trials DNA biosynthesis Diffusion 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 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 Therapeutic Therapeutic Monoclonal Antibodies Toxic effect United States National Institutes of Health Variant Vertebral column X-Ray Crystallography Yeasts barrier to care blood-brain barrier crossing blood-brain barrier penetration blood-brain barrier permeabilization brain cell chemical property chemical synthesis delivery vehicle design design,build,test 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.

项目概要用于治疗阿尔茨海默病和基于肽、蛋白质和核酸的新兴疗法血脑屏障（BBB）阻止其他神经系统疾病扩散到大脑。该项目的长期目标是使用设计的方法将诸如此类的大量治疗货物输送到大脑中跨越 BBB 的药物输送工具的总体目标是 (i) 利用近期的突破。计算肽设计，以产生有关 BBB 渗透性的新知识，以及 (ii) 从头开始设计新蛋白质通过利用大脑用来接收营养的自然系统将货物运送到大脑中和信号的中心假设是功能生物分子的系统设计将产生新的结果。改善大生物分子疗法向大脑输送的见解和工具具体目标。 1）系统合理地发现赋予BBB通透性的理化性质设计肽大环化合物（一种有前途的新型疗法）；2）通过计算设计小的、超稳定蛋白质，与 BBB 的血液侧和大脑侧之间自然循环的受体结合； 3)将目标2中产生的结合蛋白与各种药物结合/包装蛋白融合，从而创建将大量治疗药物输送到大脑中的蛋白质组装体，因为它是创新的。提出解决神经系统疾病治疗的长期障碍（即治疗困难）通过从头开始设计新的穿过血脑屏障的药物输送载体，将治疗药物输送到大脑中。该项目意义重大，因为预计它将提供能够改善未来一系列结果的工具需要输送到大脑的疗法的临床试验。