Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI

激素干预保护轴突髓磷脂，促进 SCI 功能恢复

• 批准号: 10291814
• 负责人: NAREN L BANIK
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291814
• 关键词: Acute; Animal Model; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Attenuated; Axon; Biological Availability; Calcium Signaling; Cell Differentiation process; Cell Maturation; Cells; Chronic; Cicatrix; Clinical; Clinical Trials; Data; Dose; Drug Delivery Systems; Epithelial; Estrogens; Exposure to; Extracellular Matrix; Fibroblasts; Formulation; Gait; General Population; Glial Fibrillary Acidic Protein; Gliosis; Goals; Grant; Growth Factor; Hormonal; Hormones; Human; Immune; In Vitro; Inflammation; Inflammatory; Injections; Injury; Intervention; Lesion; Methylprednisolone; Microglia; Modeling; Myelin; Natural regeneration; Neuroglia; Neurons; Neuroprotective Agents; Oligodendroglia; Phase; Pilot Projects; Plasma; Production; Rattus; Recovery of Function; Regenerative capacity; Route; Safety; Sepharose; Signal Transduction; Spinal Cord; Spinal cord injury; T cell response; Techniques; Testing; Th1 Cells; Therapeutic; Therapeutic Agents; Tissues; Translations; Treatment Efficacy; Vascular Endothelial Growth Factors; Veterans; Vimentin; angiogenesis; established cell line; estrogenic; functional improvement; glial cell-line derived neurotrophic factor; immunoregulation; improved; medication safety; myelination; nano; nanoparticle; nanoparticle delivery; neuroprotection; novel; novel marker; novel strategies; oligodendrocyte precursor; precursor cell; preservation; primary endpoint; protective effect; side effect; therapeutically effective; tissue regeneration

Estrogen (E2) treatment is known to be neuroprotectant in spinal cord injury (SCI). This hormone is highly pleiotropic and has been shown to decrease apoptosis, modulate calcium signaling, regulate growth factor expression, act as an anti-inflammatory, and can drive angiogenesis. These beneficial effects were found at the low dose of 10μg/kg E2 (multiple i.v. injections; previous grant), which helped in obtaining IND approval for taking this into a small clinical safety trial. However, the dose remains non-physiologic and thereby poses a safety hurdle for clinical use. The emergence of smart drug delivery techniques, such as nanoparticles, may allow for increased drug safety and improved efficacy. Thus, the goal of this study is to investigate the effects of nanoparticle delivery of lower doses of E2 (2.5-5.0µg, single dose) that may avoid the high systemic exposures seen with traditional dose routes (i.v. or i.p.) and allow for enhanced protective and reparative effects on lesioned tissue. Preliminary data show that a single administration of rapid release formulated PLGA-PEG nanoparticles loaded with E2 can focally deliver E2 to the contused spinal cord with reduced plasma concentrations when compared with i.v. dosing and can drive estrogenic changes. Additionally, this approach has shown that a single 5.0µg dose of nanoparticle E2 (N-E2) can improve locomotor function recovery. Pilot data suggest that E2 supports the survival of oligodendrocyte precursor cells (OPC) when exposed to toxic factors from Th1 cells and microglia in vitro. Thus, using a cocktail of rapid and slow release nanoparticle formulations, an entirely novel approach, enhanced efficacy may be achieved after SCI. This approach may allow for rapid translation of this known neuroprotectant into clinical trials. We hypothesize that focal delivery of estrogen via nanoparticles will minimize plasma exposure and increase tissue concentrations thereby allowing for maximized therapeutic potential in SCI. To test the hypothesis, three specific aims are proposed: (1) Examine N-E2 release profile and estrogenic effects on inflammation, gliosis, and neuronal protection in acute SCI; (2) Determine the mechanisms of E2-driven protective effects on epithelial, glial and neuronal cells following slow release N-E2 in acute and chronic SCI; and (3) Investigate the potential additive effects of rapid and slow release N-E2 on reduced glial scarring, enhanced regeneration, and improved locomotor function in chronic SCI. Completion of this study will identify the optimal dosing strategy of E2 loaded nanoparticles for delivery of this therapeutic agent in SCI. Additionally, as novel targets of E2 signaling are explored, progress in understanding the mechanisms of estrogenic driven neuroprotection will be made. These data should provide sufficient evidence to support the translation of E2 into clinical trials, with the ultimate goal of providing a safe and effective therapeutic to treat both veterans and the general population suffering from SCI.

雌激素（E2）治疗已知是脊髓损伤（SCI）的神经保护剂。这种激素是高度 具有多效性，并已显示可减少细胞凋亡，调节钙信号传导，调节生长因子 表达，充当抗炎剂，并且可以驱动血管生成。这些有益的影响被发现在 10μg/kg E2的低剂量（多次静脉注射;先前的授权），这有助于获得IND批准， 将其用于一个小型的临床安全性试验。然而，该剂量保持非生理性，从而造成 临床使用的安全性障碍。智能药物输送技术的出现，如纳米颗粒， 允许增加药物安全性和改善功效。因此，本研究的目的是调查 低剂量E2（2.5-5.0µg，单次给药）的纳米颗粒递送，可避免高全身性 传统给药途径（静脉注射或腹腔注射）中观察到的暴露并允许增强保护和修复 对受损组织的影响。初步数据显示，单次给药的快速释放配方 载有E2的PLGA-PEG纳米颗粒可以将E2局部递送到挫伤的脊髓， 当与静脉内给药相比时，血浆浓度降低，并且可以驱动雌激素变化。而且这个 一种方法表明，单次5.0μg剂量的纳米颗粒E2（N-E2）可以改善运动功能 复苏初步数据表明，E2支持少突胶质前体细胞（OPC）的存活， 暴露于体外Th 1细胞和小胶质细胞的毒性因子。因此，使用快速和缓慢释放的混合物， 纳米颗粒制剂，一种全新的方法，可以在SCI后实现增强的功效。这 这种方法可以使这种已知的神经保护剂快速转化为临床试验。我们假设 通过纳米颗粒集中递送雌激素将使血浆暴露最小化， 浓度，从而允许SCI中的最大治疗潜力。为了验证这个假设， 提出了具体的目的：（1）检测N-E2释放曲线和雌激素对炎症，神经胶质增生， （2）确定E2驱动的保护作用的机制， 急性和慢性SCI中缓慢释放N-E2后的上皮、神经胶质和神经元细胞;（3）研究 快速和缓慢释放N-E2对减少神经胶质瘢痕形成、增强再生和 改善慢性SCI的运动功能。完成本研究将确定以下药物的最佳给药策略： E2负载的纳米颗粒用于在SCI中递送这种治疗剂。此外，作为E2的新靶点， 信号的探索，了解雌激素驱动的神经保护机制的进展将是 进行了这些数据应该提供足够的证据来支持将E2转化为临床试验， 最终目标是为退伍军人和普通人群提供安全有效的治疗方法 患SCI。