Immune-modifying nanoparticles for the treatment of traumatic brain injury

用于治疗创伤性脑损伤的免疫调节纳米颗粒

基本信息

批准号：
10027888
负责人：
JOHN A KESSLER
金额：
$ 43.33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10027888
关键词：
Accident and Emergency department Acute Address Affect American Anatomy Attenuated Behavior Binding Biopolymers Bone Marrow Brain Brain Injuries Caliber Cell Lineage Cells Charge Clinical Trials Design Cognitive Complement Complex Edema Experimental Models FDA approved Gene Expression Gliosis Glycolates Health Hematogenous Hippocampus (Brain)Hour Human Immune Infiltration Inflammation Inflammatory Injury Intervention Intravenous Label Lead Mediating Microglia Modeling Molecular Mus Neuroglia Neurons Pharmacology Physiological Population Process Reactive Oxygen Species Recovery Role Seizures Site Spleen Structure Synapses TBI treatment Temperature Time Translations Traumatic Brain Injury Travel Treatment Efficacy Tumor-infiltrating immune cells Vascular Endothelial Cell behavior influence brain tissue carboxylate cell type chemokine clinically translatable cytokine designer receptors exclusively activated by designer drugs excitotoxicity experimental study improved outcome macrophage monocyte nanoparticle neurogenesis neuronal survival particle preclinical trial preservation prevent protective effect receptor single-cell RNA sequencing stem cell proliferation stem cells therapeutic development tool visual motor

项目摘要

Traumatic Brain Injury (TBI) is a major health issue. After the primary injury, there is substantial secondary injury attributable to infiltrating immune cells, cytokine release, reactive oxygen species, excitotoxicity, and other mechanisms. Despite many preclinical and clinical trials designed to limit such secondary damage, no successful therapies have emerged. However, we have found that Immune-modifying nanoParticles (IMP) are a strong candidate for a clinically translatable acute pharmacologic intervention for TBI. IMP are highly negatively charged, 500 nm-diameter particles composed of the FDA-approved biodegradable biopolymer, carboxylated poly(lactic-co-glycolic) acid (PLGA-COOH). After intravenous (IV) administration, IMP bind to the macrophage receptor with collagenous structure (MARCO) on monocytes. Monocytes bound to IMP no longer travel to sites of inflammation, but instead are sequestered in the spleen. Because IMP specifically target the MARCO+ subset of monocytes, it is distinctly different from other approaches that non-specifically target all monocyte/macrophage lineage cells including microglia. IV treatment with IMP in two different TBI models profoundly reduced the number of immune cells infiltrating into the brain, mitigated the inflammatory status of the infiltrating cells, and reduced levels of an array of cytokines and chemokines. More importantly, IMP treatment resulted in attenuated edema, preservation of brain tissue, and significant preservation of both physiologic visual and motor function. The proposed studies will examine IMP-mediated changes in gene expression that alter the inflammatory status of infiltrating cells, limit gliosis, reduce edema, and promote neuronal survival. They also will examine effects of IMP on other cell types including microglia, progenitor cells, and other immune cells. Notably, IMP are made of an FDA-approved material that is stable at room temperature and could easily be given immediately IV after TBI in the field by EMTs or in the emergency room. Mechanistically the proposed studies will help to understand more clearly the effects of infiltrating hematogenous monocyte-derived macrophages after TBI. Significantly, they also will help to develop a potentially effective and practical therapy for human TBI.

创伤性脑损伤（TBI）是一个重大的健康问题。原发性损伤后，存在严重的继发性损伤归因于浸润免疫细胞、细胞因子释放、活性氧、兴奋性毒性和其他机制。尽管许多临床前和临床试验旨在限制这种继发性损害，但没有成功疗法已经出现。然而，我们发现免疫修饰纳米粒子（IMP）是一种强大的 TBI 临床可转化急性药物干预的候选者。 IMP 持高度负面态度带电、直径 500 nm 的颗粒由 FDA 批准的可生物降解生物聚合物组成，羧化聚乳酸-乙醇酸 (PLGA-COOH)。静脉 (IV) 给药后，IMP 与巨噬细胞结合单核细胞上具有胶原结构（MARCO）的受体。与 IMP 结合的单核细胞不再前往部位炎症，而是被隔离在脾脏中。因为 IMP 专门针对 MARCO+ 子集单核细胞，它与非特异性靶向所有单核细胞/巨噬细胞的其他方法明显不同谱系细胞，包括小胶质细胞。在两种不同的 TBI 模型中使用 IMP 进行 IV 治疗显着降低了浸润大脑的免疫细胞数量，减轻浸润细胞的炎症状态，以及一系列细胞因子和趋化因子的水平降低。更重要的是，IMP 治疗可减弱水肿，保留脑组织，并显着保留生理视觉和运动功能。拟议的研究将检查 IMP 介导的基因表达变化，从而改变炎症状态浸润细胞，限制神经胶质增生，减少水肿，促进神经元存活。他们还将检查的影响对其他细胞类型（包括小胶质细胞、祖细胞和其他免疫细胞）进行 IMP。值得注意的是，IMP 是由一种经 FDA 批准的材料，在室温下稳定，可在 TBI 后立即轻松静脉注射急救人员在现场或在急诊室。从机制上讲，拟议的研究将有助于理解更清楚地了解 TBI 后浸润的血源性单核细胞衍生巨噬细胞的影响。显著地，他们还将帮助开发一种潜在有效且实用的人类 TBI 疗法。