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Engineered extracellular vesicles as a targeted drug delivery system for multiple sclerosis

工程细胞外囊泡作为多发性硬化症的靶向药物递送系统

基本信息

批准号：
10387930
负责人：
Rachel Mizenko
金额：
$ 3.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387930
关键词：
Address Area Autoimmune Biodistribution Biological Assay Biological Availability Biomimetics Blocking Antibodies Blood - brain barrier anatomy Cell Differentiation process Cells Clinical Trials Coculture Techniques Data Demyelinations Development Differentiation Inducer Disease Disease Progression Drug Delivery Systems Drug Targeting Dyes Electroporation Endothelium Engineering Exhibits Experimental Autoimmune Encephalomyelitis Extracellular Protein Fluorescence Goals Heterogeneity Immune Targeting In Vitro Individual Inflammation Knowledge Label Laboratories Lesion Liposomes Mediating Medical Membrane Proteins Methods MicroRNAs Modeling Molecular Multiple Sclerosis Myelin National Research Service Awards Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurology Oligodendroglia Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Population Proteins Recovery Reporting Resources Sorting - Cell Movement Source Surface System Technical Expertise Techniques Testing Therapeutic Tissues Training Universities Untranslated RNA Vesicle blood-brain barrier crossing blood-brain barrier penetration blood-brain barrier permeabilization brain endothelial cell career cell type clinical translation delivery vehicle density detection limit effective therapy extracellular vesicles in vivo in vivo evaluation interest nanoparticle nanoparticle drug next generation novel therapeutics oligodendrocyte precursor oligodendrocyte progenitor precursor cell prevent protein expression receptor remyelination stem cells synthetic drug therapeutically effective trafficking transcytosis translational medicine uptake

项目摘要

Abstract The ultimate goal of this F31 Ruth L. Kirchstein NRSA is to request support to address a fundamental gap in knowledge preventing engineering of efficacious drug delivery vehicles for progressive multiple sclerosis (PMS). PMS is a common, debilitating neurodegenerative disease that causes widespread demyelination in the central nervous system. There are currently no therapies that reliably remediate the advance of PMS, but an emerging strategy is to promote recovery by initiating differentiation of oligodendrocyte progenitor cells (OPCs) to oligodendrocytes, the myelin producing cells depleted in PMS. Current drug delivery techniques to achieve remyelination are either poorly efficacious or highly invasive, major impediments to clinical translation. An effective remyelinating therapeutic for PMS must cross the intact blood-brain barrier (BBB) and then target OPCs. This proposal focuses on the synthesis and testing of engineered extracellular vesicles (eEVs) as a drug delivery vehicle to accomplish these feats. Natural EVs have been shown to both target specific cells/tissues and also cross endothelial barriers. However, due to their immense functional heterogeneity, these qualities do not occur in the same EVs. Although a population of EVs that efficiently targets OPC has been identified, the best EV population and key proteins that promote BBB crossing remain unknown, preventing new biomimetic engineering strategies. To address the limitations of current therapeutics, I propose to identify and fuse subpopulations of EVs that efficiently cross the BBB and target OPCs, load them with microRNA-219, an OPC differentiating agent, to engineer a bioavailable and selective drug delivery vehicle. Building on results obtained in my preliminary data, I will carry out this project in three steps: (1) to optimize a method of fluorescence activated vesicle sorting to identify and isolate BBB-crossing EVs; (2) to elucidate the molecular mechanisms and key proteins during BBB transcytosis using a functional transwell model; and (3) to produce eEVs via fusion of endogenous EVs and loading with remyelinating therapeutics. We will quantify eEV ability to cross the BBB and target OPCs to initiate differentiation and produce myelin in vitro and in vivo. This project is focused on producing a novel therapeutic uniquely suited to PMS, but this pipeline to engineer EVs with multiple targeted functions could be applied to address drug delivery barriers for many medical problems. This project was developed in parallel with a rigorous training plan to enhance my training and technical skills in the areas of neurology, pharmacology, and translational medicine. This plan will enable my transition to independence as I focus on my long-term goal of pursuing an academic career developing neurological therapeutics. Training will exploit the university’s many resources for professional and educational development.

摘要