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.

众所周知，雌激素 (E2) 治疗对于脊髓损伤 (SCI) 具有神经保护作用。这种激素含量很高 具有多效性，已被证明可以减少细胞凋亡、调节钙信号传导、调节生长因子 表达，起到抗炎作用，并可以驱动血管生成。这些有益效果被发现于 10μg/kg E2 的低剂量（多次静脉注射；之前的资助），这有助于获得 IND 批准 将此纳入小型临床安全试验。然而，该剂量仍然是非生理性的，因此构成了 临床使用的安全障碍。纳米颗粒等智能药物输送技术的出现可能会 可以提高药物安全性并提高疗效。因此，本研究的目的是调查影响 纳米粒子递送较低剂量的 E2（2.5-5.0μg，单剂量），可以避免高全身性 传统剂量途径（静脉注射或腹腔注射）所见的暴露，并可增强保护和修复作用 对病变组织的影响。初步数据表明，单次给药快速释放制剂 负载 E2 的 PLGA-PEG 纳米颗粒可以将 E2 集中递送至挫伤的脊髓，同时减少 与静脉注射相比的血浆浓度剂量并可以驱动雌激素的变化。另外，这 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 恢复。试验数据表明，E2 支持少突胶质细胞前体细胞 (OPC) 的存活 体外暴露于 Th1 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 纳米颗粒制剂是一种全新的方法，在 SCI 后可能会提高疗效。这 该方法可能允许将这种已知的神经保护剂快速转化为临床试验。我们假设 通过纳米粒子集中输送雌激素将最大限度地减少血浆暴露并增加组织 浓度，从而最大限度地发挥 SCI 的治疗潜力。为了检验假设，三个 提出了具体目标：（1）检查 N-E2 释放曲线和雌激素对炎症、神经胶质增生、 以及急性 SCI 中的神经元保护； (2) 确定E2驱动的保护作用机制 急性和慢性 SCI 中缓慢释放 N-E2 后的上皮细胞、神经胶质细胞和神经元细胞； (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 改善慢性 SCI 的运动功能。完成本研究将确定最佳剂量策略 E2 负载纳米粒子用于在 ​​SCI 中递送这种治疗剂。此外，作为 E2 的新目标 探索信号传导，了解雌激素驱动的神经保护机制将取得进展 制成。这些数据应该提供足够的证据来支持E2转化为临床试验， 最终目标是为退伍军人和普通民众提供安全有效的治疗方法 患有SCI。