Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury

功能化酶治疗脊髓损伤炎症的双重靶向

• 批准号: 10284992
• 负责人: Benjamin George Keselowsky
• 金额: $ 41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284992
• 关键词: Acute; Anti-Inflammatory Agents; Astrocytes; Autoimmune; Binding; Binding Proteins; Blood; Blood Circulation; Carbohydrates; Cause of Death; Cell Death; Cells; Chronic; Cicatrix; Clinical; Complex; Cues; Deposition; Dioxygenases; Down-Regulation; Engineering; Enzymes; Extracellular Matrix; FDA approved; Feedback; Formulation; Galectin 3; Glycosaminoglycans; Goals; Growth; Homeostasis; Hour; Human body; Hydrogels; Immune; Immune response; Immunomodulators; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injections; Injury; Intravenous; Kynurenine; Lesion; Leukocytes; Liver; Methylprednisolone; Microglia; Modification; Mus; Muscle; Natural regeneration; Nerve; Neuraxis; Neuroglia; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Polyethylene Glycols; Polysaccharides; Process; Production; Prognosis; Property; Protein Engineering; Proteins; Psoriasis; Recombinant Proteins; Recombinants; Recovery of Function; Regimen; Reperfusion Injury; Research; Site; Skin; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Spinal cord injury patients; Steroids; Target Populations; Therapeutic; Therapeutic Effect; Time; Tissues; Translations; Trauma; Traumatic CNS injury; Tryptophan; Tryptophan 2,3 Dioxygenase; Up-Regulation; Work; axon regeneration; central nervous system injury; cost; cytokine; design; disability; effective therapy; efficacy testing; enzyme therapy; glial activation; healing; hydrogel scaffold; immunoregulation; improved; indoleamine; inhibitor/antagonist; innovation; intravenous administration; macrophage; monocyte; neuroinflammation; neutrophil; novel; novel strategies; novel therapeutics; pre-clinical research; public health relevance; regenerative; regenerative cell; relating to nervous system; repaired; response; scaffold; standard of care; systemic inflammatory response; tissue repair; wound healing

PROJECT SUMMARY Unlike other tissues, such as skin and muscle that are capable of complete tissue remodeling, the central nervous system (CNS) lacks the ability to properly heal after injury. Instead, CNS wound repair is marked by sustained glial reactivity and scar tissue deposition, all of which are exacerbated by inflammation. Therapeutic application of the anti-inflammatory methylprednisolone is the only current treatment option for spinal cord injury (SCI), however, it only has acute efficacy and does not resolve tissue remodeling or scarring. This project proposes to investigate idoleamine 2,3-dioxygenase (IDO) as a novel immunomodulatory therapeutic for SCI. IDO is attractive for its dual targeting ability not only to downregulate pro-inflammatory responses but also to promote pro-regenerative cell phenotypes, effectively restoring the imbalance of inflammatory processes after CNS injury. The guiding hypothesis of this research is that IDO will have dual efficacy in immunomodulation of acute systemic inflammation and mitigation of chronic resident cell activation and scarring in the spinal cord. Moreover, the project will investigate two innovative, functionalized forms of IDO for directed targeting of systemic and localized immunomodulation in SCI. First, IDO modified with polyethylene glycol (PEG) will be used for systemic intravenous administration immediately after SCI. PEG improves protein stability in blood and prolongs circulation time, making it an ideal candidate for systemic delivery. PEG-IDO will target circulating leukocytes to modulate early stage inflammation after injury. Secondly, IDO fused with galectin- 3 (Gal3), a glycan binding protein to increase local retention at a tissue target site, will be delivered one week after injury to evaluate effects on resident cell reactivity, reparative immune cell presence, and tissue scarring. The rationale for this design is to better harness IDO’s ability to promote reparative mechanisms in immune cells and glia that are locally present around the lesion site. Co-administration of IDO-Gal3 with key compounds that direct production of neuroprotective metabolites by resident glia (i.e., KMO inhibitors) will further enhance therapeutic effects of localized IDO. Together, this combination will be delivered within a novel, pro-regenerative decellularized neural scaffold to synergistically mitigate neuroinflammation. Overall, the dual immunomodulation potential of IDO provides a new perspective for anti-inflammatory drug administration for CNS injury. The proposed work will demonstrate merit for the individual novel approaches with PEG-IDO and IDO-Gal3 for cell-specific targeting. The long-term goal is to use this mechanistic understanding as a first step in research efforts to develop more effective combination strategies for CNS repair.

项目概要 与其他组织（例如皮肤和肌肉）能够完全重塑组织不同，中枢 神经系统 (CNS) 受伤后缺乏正常愈合的能力。相反，中枢神经系统伤口修复的特点是 持续的神经胶质反应和疤痕组织沉积，所有这些都会因炎症而加剧。治疗性 抗炎甲基泼尼松龙的应用是目前治疗脊髓损伤的唯一选择 （SCI），然而，它仅具有急性功效，不能解决组织重塑或疤痕。 该项目拟研究偶像胺 2,3-双加氧酶 (IDO) 作为一种新型免疫调节剂 SCI 的治疗。 IDO 的吸引力在于其双重靶向能力，不仅可以下调促炎症因子 反应还可以促进促再生细胞表型，有效恢复细胞的不平衡 中枢神经系统损伤后的炎症过程。本研究的指导性假设是 IDO 将具有双重功能 对急性全身炎症的免疫调节和减轻慢性常驻细胞活化的功效 以及脊髓中的疤痕。此外，该项目将研究 IDO 的两种创新、功能化形式 用于 SCI 中全身和局部免疫调节的定向靶向。一、IDO用聚乙烯改性 SCI 后立即使用乙二醇 (PEG) 进行全身静脉注射。 PEG改善蛋白质 血液稳定性并延长循环时间，使其成为全身给药的理想选择。 PEG-IDO将 靶向循环白细胞以调节损伤后的早期炎症。其次，IDO 与半乳糖凝集素融合 3 (Gal3) 是一种聚糖结合蛋白，可增加组织目标部位的局部保留，将在一周内交付 损伤后评估对常驻细胞反应性、修复性免疫细胞存在和组织疤痕的影响。 这种设计的基本原理是更好地利用 IDO 促进免疫修复机制的能力 病变部位周围局部存在的细胞和神经胶质细胞。 IDO-Gal3 与关键化合物的共同给药 常驻神经胶质细胞（即 KMO 抑制剂）直接产生神经保护代谢物将进一步增强 局部IDO的治疗效果。总之，这种组合将在一种新颖的、促再生的 脱细胞神经支架可协同减轻神经炎症。 总体而言，IDO的双重免疫调节潜力为抗炎药物提供了新的视角 中枢神经系统损伤的给药。拟议的工作将证明各个新方法的优点 用于细胞特异性靶向的 PEG-IDO 和 IDO-Gal3。长期目标是利用这种机械理解 作为开发更有效的中枢神经系统修复组合策略的研究工作的第一步。