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

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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.