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.

项目摘要 与其他时间（例如能够完成组织重塑的皮肤和肌肉）不同，中央 神经系统（CNS）缺乏受伤后正确愈合的能力。相反，CNS伤口维修是由 持续的神经胶质反应性和疤痕组织沉积，所有这些都因炎症而加剧。治疗性 抗炎甲基强酮的应用是脊髓损伤的唯一治疗选择 （SCI）但是，它仅具有急性效率，并且不能解决组织重塑或疤痕。 该项目的提议旨在研究偶像偶像胺2,3-二氧酶（IDO）作为一种新型免疫调节 科学疗法。 IDO的双重靶向能力不仅可以下调促炎的能力 反应，但也促进促进再生细胞表型，有效地恢复了不平衡 CNS损伤后的炎症过程。这项研究的指导假设是IDO将有双重 急性全身炎症免疫调节的功效和慢性居民细胞激活的缓解 并在脊髓中疤痕。此外，该项目将研究IDO的两种创新，功能化形式 用于针对SCI中系统性和局部免疫调节的靶向。首先，用聚乙烯修饰的IDO SCI后立即将甘油（PEG）用于全身静脉内给药。 PEG改善蛋白质 血液的稳定性并延长循环时间，使其成为全身传递的理想候选者。 PEG-IDO会 靶标循环白细胞受伤后调节早期注射。其次，伊多与乳糖素融合 3（GAL3）是一种聚糖结合蛋白，以增加组织目标部位的局部保留率，将交付一周 损伤后，以评估对居民细胞反应性的影响，修复性免疫球的存在和组织疤痕。 这种设计的理由是更好地利用Ido促进免疫力修复机制的能力 病变部位周围存在的细胞和神经胶质。 IDO-GAL3与关键化合物的共同给药 居民神经胶质（即KMO抑制剂）直接生产神经保护代谢产物将进一步增强 局部IDO的治疗作用。这种组合将在小说，促进性中交付 脱细胞化神经外体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提供了新的视角 中枢神经系统损伤给药。拟议的工作将证明对单个新颖方法的优点 PEG-IDO和IDO-GAL3用于细胞特异性靶向。长期目标是利用这种机械理解 作为研究CNS维修更有效组合策略的研究工作的第一步。