Targeted Therapies for Neonatal White Matter Injury

新生儿脑白质损伤的靶向治疗

• 批准号: 9916819
• 负责人: S. Ali Fatemi
• 金额: $ 41.36万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916819
• 关键词: Acetylcysteine; Address; Adult; Affect; Animal Model; Animals; Astrocytes; Attenuated; Axon; Behavioral; Biodistribution; Brain; Brain Injuries; Brain imaging; Cell Transplantation; Cerebral Palsy; Child; Chronic; Cysteine; Dendrimers; Developmental Disabilities; Diffuse; Diffuse Brain Injury; Disease; Disulfides; Dose; Drug Delivery Systems; Drug Targeting; Early Diagnosis; Environment; Esters; Fluorescence; Histology; Hour; Hybrids; Hypoxia; Image; Immunohistochemistry; Inflammation; Inflammatory; Injury; Institutes; Intellectual functioning disability; Intervention; Intravenous; Ischemia; Knowledge; Label; Mediating; Medicine; Methods; Microglia; Modeling; Mus; Myelin; Nanostructures; Nanotechnology; Natural regeneration; Neonatal; Neonatal Brain Injury; Neurodevelopmental Disability; Neurologic; Neurological outcome; Neurology; Oligodendroglia; Organ; Outcome; Oxidative Stress; Pathogenesis; Pharmaceutical Preparations; Pharmacotherapy; Polymers; Preparation; Proteins; Public Health; Research; Role; Systemic Therapy; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transgenic Mice; Translational Research; Transplantation; Trees; astrogliosis; attenuation; axon injury; base; behavior test; brain repair; cellular targeting; clinically relevant; cortical visual impairment; cyanine dye 5; cytokine; density; design; improved; injury and repair; intrauterine infection; intravenous administration; macrophage; migration; mouse model; myelination; nanodevice; nanomedicine; nanotherapy; neonatal hypoxic-ischemic brain injury; neonate; nervous system disorder; neurobehavioral; neuroinflammation; novel therapeutics; post-transplant; postnatal; postnatal period; precursor cell; premature; targeted treatment; therapy outcome; uptake; white matter injury

PROJECT SUMMARY ABSTRACT Neonatal White Matter Injury (NWMI) is the leading cause of neurologic and developmental disabilities in children born prematurely. Neuroinflammation, following an initial ischemic/hypoxic-ischemic or infectious insult, mediated by activated microglia and astrocytes, is implicated in the pathogenesis resulting in diffuse white matter injury. Targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. However, delivery of drugs for the treatment of diffuse brain injury in the neonate is a major challenge. Our preliminary studies suggest that intravenous administration of dendrimers (tree-like nanostructured polymers, 4 nm) results in their selective accumulation in activated microglia/macrophages and astrocytes in the brain of injured animals. Importantly, a single, intravenous 10 mg/kg dose of N-acetyl cysteine (NAC) conjugated to the dendrimer (D-NAC), administered after neonatal ischemia resulted in a significant improvement in myelination in the short-term, and attenutation of neuroinflammation. First, we seek to attenuate neuroinflammation in NWMI in a targeted manner. However, target drug delivery for the treatment of diffuse brain injury is a major challenge. We have previously shown that systemic administration of dendrimers (tree-like nanostructured polymers, 4nm) results in their selective accumulation in activated microglia and astrocytes, and in oligodendrocytes in our ischemic NWMI mouse model. Furthermore, dendrimer conjugated to N-acetylcysteine (D-NAC), systemically administered at 24h and 5 days post neonatal ischemia, resulted in sustained attenuation of inflammatory cytokines and reduction of white matter injury at postnatal day 14. Second, we seek to use targeted D-NAC nanotherapy to improve Glial restricted precursor (GRP) survival. GRP cell transplantation is currently being investigated as a therapeutic strategy in a number of neurologic diseases, and we have previously shown that transplanted GRPs exert some restorative effect in the same ischemic mouse model of NWMI, but have limited survival and differentiation capacity when injected into injured brain. Building on these promising findings, the objective of this application is to (i) provide sustained drug release by D-NAC to prolong therapeutic effect, (ii) determine the therapeutic window for D-NAC treatment in the postnatal period and (iii) determine whether D-NAC can enhance survival and restorative capacity of transplanted GRP cells. Our hypotheses are that (1) ongoing neuroinflammation will facilitate selective accumulation of D-NAC in activated microglia/macrophages and astrocytes even at later time points following neonatal ischemia in NWMI; (2) Targeted cellular delivery and sustained release of NAC by dendrimer nanodevices will result in (a) reduction of neuroinflammation/oxidative stress, and (b) improve long term neurobehavioral and neuropathological outcomes in NWMI; (3) D-NAC therapy will reduce inflammation and oxidative stress and allow a permissive environment for GRPs to survive, migrate and restore myelination and axonal injury in NWMI. These hypotheses will be tested using three specific aims, relating to the preparation of dendrimer-NAC nanodevice, identifying the therapeutic window in the post-natal period, and assessing the sustained efficacy of dendrimer. This study is significant because, it explores the potential of targeted post-natal therapy in a clinically relevant model of NWMI for improvement in neurological outcomes, and it will help us to develop a better understanding of how modulating the role of microglial activation and chronic neuroinflammation affects neonatal brain injury and the capacity of precursor cells to remyelinate an injured brain.

项目概要摘要 新生儿白质损伤（NWMI）是新生儿神经系统和发育障碍的主要原因 早产儿。最初的缺血/缺氧缺血或感染后的神经炎症 由活化的小胶质细胞和星形胶质细胞介导的损伤与导致弥漫性损伤的发病机制有关 白质损伤。减轻神经炎症的靶向药物输送可能会大大提高治疗效果 结果。然而，治疗新生儿弥漫性脑损伤的药物输送是一个重要的领域。 挑战。我们的初步研究表明静脉注射树枝状聚合物（树状聚合物） 纳米结构聚合物，4 nm）导致它们在活化的小胶质细胞/巨噬细胞中选择性积累， 受伤动物大脑中的星形胶质细胞。重要的是，单次静脉注射 10 mg/kg 剂量的 N-乙酰半胱氨酸 (NAC) 与树枝状大分子 (D-NAC) 缀合，在新生儿缺血后施用，导致显着的 短期内改善髓鞘形成，并减轻神经炎症。首先，我们寻求 有针对性地减轻 NWMI 的神经炎症。然而，用于治疗的靶向药物递送 弥漫性脑损伤是一个重大挑战。我们之前已经表明，树枝状聚合物的全身给药 （树状纳米结构聚合物，4nm）导致它们在激活的小胶质细胞中选择性积累， 星形胶质细胞和我们的缺血性 NWMI 小鼠模型中的少突胶质细胞。此外，树枝状聚合物缀合 N-乙酰半胱氨酸（D-NAC），在新生儿缺血后 24 小时和 5 天全身给药，导致 出生后第 14 天炎症细胞因子持续减弱并减少白质损伤。 其次，我们寻求使用靶向 D-NAC 纳米疗法来提高胶质细胞限制性前体 (GRP) 的存活率。 目前正在研究 GRP 细胞移植作为许多神经系统疾病的治疗策略 疾病，我们之前已经表明，移植的 GRP 在相同的疾病中发挥了一些恢复作用 NWMI 缺血小鼠模型，但注射后存活和分化能力有限 受伤的大脑。基于这些有希望的发现，本应用的目标是 (i) 提供持续的 D-NAC 释放药物以延长治疗效果，(ii) 确定 D-NAC 的治疗窗 产后治疗以及 (iii) 确定 D-NAC 是否可以提高生存率和恢复能力 移植的 GRP 细胞的能力。我们的假设是（1）持续的神经炎症将促进 即使在较晚的时间点，D-NAC 在活化的小胶质细胞/巨噬细胞和星形胶质细胞中选择性积累 NWMI 新生儿缺血后； (2) NAC的靶向细胞递送和缓释 树枝状聚合物纳米器件将导致（a）减少神经炎症/氧化应激，以及（b）改善长期 NWMI 的术语神经行为和神经病理学结果； (3) D-NAC治疗可减轻炎症 和氧化应激，并为 GRP 生存、迁移和恢复髓鞘形成提供宽松的环境 和 NWMI 的轴突损伤。这些假设将使用三个具体目标进行检验，涉及 制备树枝状聚合物-NAC纳米器件，确定产后治疗窗口，以及 评估树枝状聚合物的持续功效。这项研究意义重大，因为它探讨了 在 NWMI 临床相关模型中进行有针对性的产后治疗，以改善神经系统结果， 它将帮助我们更好地理解如何调节小胶质细胞激活和 慢性神经炎症影响新生儿脑损伤和前体细胞髓鞘再生能力 受伤的大脑。