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.

已知雌激素（E2）治疗在脊髓损伤（SCI）中是神经保护剂。这匹马很高 多效性，已显示可降低凋亡，调节钙信号传导，调节生长因子 表达，充当抗炎，可以驱动血管生成。在 低剂量的10μg/kg E2（多次i.v.注射；先前的赠款），有助于获得IND批准 将其带入小型临床安全试验。但是，剂量仍然是非生理学的，从而定位a 临床使用的安全障碍。智能药物输送技术（例如纳米颗粒）的出现可能 允许提高药物安全性并提高效率。这是这项研究的目的是研究效果 低剂量的E2（2.5-5.0µg，单剂量）的纳米颗粒输送可能避免了高度全身性 传统剂量路线（i.v.或i.p.）看到的暴露 对病变组织的影响。初步数据表明，快速释放的单一管理 带有E2的PLGA-PEG纳米颗粒可以将E2聚焦为持续的脊髓，并减少 与静脉相比，血浆浓度剂量并可以驱动雌激素变化。另外，这个 方法表明，单个5.0μg纳米颗粒E2（N-E2）可以改善运动功能 恢复。试验数据表明，E2支持少突胶质细胞前体细胞（OPC）的生存 在体外暴露于Th1细胞和小胶质细胞的有毒因素。那是使用快速和缓慢释放的鸡尾酒 纳米颗粒公式是一种完全新颖的方法，在SCI后可以提高效率。这 方法可能可以将这种已知神经保护剂快速转换为临床试验。我们假设 通过纳米颗粒的雌激素的焦点递送将使血浆暴露最小化并增加组织 因此浓度允许SCI中的最大热势。为了检验假设，三个 提出了具体目的：（1）检查N-E2释放曲线和雌激素对注射，神经胶质的影响， 和急性科幻的神经元保护； （2）确定E2驱动的受保护作用的机制 在急性和慢性科学中缓慢释放N-E2后，上皮，神经胶质和神经元细胞； （3）调查 快速和缓慢释放N-E2对减少神经胶质疤痕，增强再生和 改善了慢性科学的运动功能。这项研究的完成将确定 E2加载了用于在SCI中递送该治疗剂的纳米颗粒。另外，作为E2的新目标 探索了信号，了解雌激素驱动神经保护的机制的进展将是 制成。这些数据应提供足够的证据，以支持E2转化为临床试验 提供安全有效的治疗退伍军人和普通人群的最终目标 患有科幻。