Designed Vehicles for Blood Brain Barrier Traversal

设计用于穿越血脑屏障的车辆

• 批准号: 9796948
• 负责人: DAVID BAKER
• 金额: $ 53.58万
• 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/9796948
• 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; Penetration; 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; 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.

项目总结