Designed Vehicles for Blood Brain Barrier Traversal

设计用于穿越血脑屏障的车辆

• 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
• 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' 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

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 用于治疗阿尔茨海默病和阿尔茨海默病的新兴的基于肽、蛋白质和核酸的治疗剂 血脑屏障（BBB）阻止其它神经病症扩散到脑中。的 该项目的长期目标是使用设计的药物将这些大型治疗药物输送到大脑中。 穿越血脑屏障的药物运输工具。总体目标是：（一）利用最近的突破， 计算肽设计，以产生关于BBB渗透性的新知识，以及（ii）从头开始设计 新的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 和信号。核心假设是功能生物分子的系统设计将产生新的 研究人员正在研究用于改善大生物分子治疗剂向大脑中递送的见解和工具。具体目标 主要有：1）系统合理地发现影响血脑屏障通透性的理化性质 设计肽大环化合物（一类有前途的新治疗剂）; 2）计算设计小的， 超稳定蛋白质，其与在血脑屏障的血液侧和脑侧之间自然循环的受体结合; 和3）将目标2中产生的结合蛋白融合到各种药物结合/包装蛋白，从而 制造蛋白质组合体，将大型治疗药物运送到大脑中。这个项目是创新的，因为它 建议解决长期存在的障碍，以治疗神经系统疾病（即， 将治疗剂递送到大脑中）。的 该项目意义重大，因为预计它将提供工具，改善未来一系列成果。 需要输送到大脑的治疗药物的临床试验。