Treatment of Knee Osteoarthritis via Intra-articular Delivery of an Immunosuppressive Enzyme

通过关节内递送免疫抑制酶治疗膝骨关节炎

基本信息

批准号：
10597687
负责人：
Kyle D Allen
金额：
$ 63.04万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597687
关键词：
Acute Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Arthralgia Attenuated Behavior Behavioral Binding Cells Chimeric Proteins Chronic Chronic Disease Data Degenerative polyarthritis Disease Dose Drug Delivery Systems Enzymes Extracellular Matrix Future Gait Galectin 3 Histology Homeostasis Human IL6 gene Immune Immune system Inflammation Interleukin-6 Intra-Articular Injections Joints Knee Knee Osteoarthritis Kynurenine Limb structure Macrophage Medial meniscus structure Mediator Metabolic Metabolism Modeling Pain Pathogenesis Pathologic Pathway interactions Patients Persistent pain Pharmaceutical Preparations Play Process Proteins Rattus Risk Rodent Rodent Model Role Signal Transduction Source Symptoms Synovial Fluid System T-Lymphocyte Tactile Therapeutic Time Tissues Trauma Traumatic Arthropathy Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan Metabolism Pathway allodynia arthropathies carbohydrate binding protein carbohydrate receptor cytokine disability extracellular immunoengineering immunoregulation improved inflammatory pain innovation joint destruction joint inflammation joint injury meniscal tear meniscus injury novel novel therapeutic intervention osteoarthritis pain prevent residence synthetic drug treatment strategy

项目摘要

Project Summary In osteoarthritis (OA), intra-articular inflammation is a key mediator of joint destruction and chronic joint pain. Unfortunately, current strategies to control joint inflammation have largely failed. To address this challenge, our team is developing an innovative metabolic reprogramming strategy for the treatment of knee OA. In our strategy, indoleamine 2,3-dioxygenase (IDO), an immunosupressive enzyme, will be intra-articularly delivered to catabolize tryptophan into kynurenines. Based on IDO’s effect in other tissues, this redirection of tryptophan metabolism will likely drive the polarization of joint-level immune cells toward an anti-inflammatory state. Importantly, our strategy differs from other intra-articular delivery strategies for protein and synthetic drugs, as our enzyme will continuously produce anti-inflammatory metabolites in the OA-affected joint and thereby create prolonged anti-inflammatory effects that potentially reset immune homeostasis in the joint. However, while IDO can continuously produce anti-inflammatory metabolites, free IDO is subject to joint clearance. To address this challenge, we will also fuse IDO to a carbohydrate-binding protein, thereby extending IDO’s joint residence time via a novel tissue anchoring approach. Morever, because tissue-anchored IDO does not need to release to generate anti-inflammatory signals, the anchored IDO will continue to produce anti-inflammatory kyneurenines without the need for our ‘drug’ (IDO) to release and bind a specific target. Our preliminary data demonstrate that tryptophan metabolism is altered in both human OA and rodent models, our tissue anchoring strategy can extend the residence time of an enzyme from a few days to over 4 weeks, and that intra-articular delivery of an IDO fusion protein can shift tryptophan metabolism, reduce inflammation, and reverse pain-related behaviors in a rat knee OA model. As such, this R01 proposal seeks to evaluate intra-articular delivery of an IDO fusion protein as a therapeutic strategy to control joint inflammation and reduce OA-related pathological remodeling after trauma (Aim 1) and after the onset of chronic OA symptoms (Aim 2). To achieve these aims, our team will integrate expertise in metabolic profiling, immune engineering, joint histology, and rodent behavioral analyses. Specifically, this R01 will address the following scientific questions: 1) How is joint metabolism altered by intra- articular delivery of an IDO fusion protein? 2) How is the local regulation of the immune system within the joint altered by an intra-articular injection of an IDO fusion protein? 3) Do IDO-induced metabolic shifts affect other joint tissues as well? 4) Can intra-articular injection of an IDO fusion protein stall the onset of post-traumatic OA after medial meniscus injury? and, 5) Can intra-articular delivery of an IDO fusion protein reverse OA-related pain and disability, even in the context of irreparable joint damage? Answering these questions will be important for understanding the translational risks of our IDO fusion protein, as well as for refining metabolic reprogramming strategies for OA treatment in the future.

项目概要在骨关节炎（OA）中，关节内炎症是关节破坏和慢性关节疼痛的关键介质。不幸的是，目前控制关节炎症的策略基本上失败了。团队正在开发一种创新的代谢重编程策略来治疗膝关节骨关节炎。吲哚胺 2,3-双加氧酶 (IDO) 是一种免疫抑制酶，将通过关节内递送根据 IDO 在其他组织中的作用，将色氨酸分解代谢为犬尿氨酸。新陈代谢可能会推动关节级免疫细胞向抗炎状态极化。重要的是，我们的策略不同于蛋白质和合成药物的其他关节内递送策略，因为我们的酶将在受 OA 影响的关节中持续产生抗炎代谢物，从而产生长时间的抗炎作用可能会重置关节中的免疫稳态。可以持续产生抗炎代谢物，游离 IDO 需要经过联合清除才能解决这个问题。为了应对挑战，我们还将把 IDO 融合到碳水化合物结合蛋白上，从而延长 IDO 的联合停留时间此外，由于组织锚定的 IDO 不需要释放到产生抗炎信号，锚定的IDO将持续产生抗炎犬神经氨酸不需要我们的“药物”（IDO）来释放和结合特定的目标。我们的初步数据证明了这一点。色氨酸代谢在人类 OA 和啮齿动物模型中都发生了改变，我们的组织锚定策略可以扩展酶的停留时间从几天到超过 4 周，以及 IDO 的关节内输送融合蛋白可以改变大鼠的色氨酸代谢、减少炎症并逆转与疼痛相关的行为因此，该 R01 提案旨在评估 IDO 融合蛋白的关节内递送。控制关节炎症并减少创伤后 OA 相关病理重塑的治疗策略（目标 1）和慢性 OA 症状出现后（目标 2），我们的团队将进行整合。代谢分析、免疫工程、关节组织学和啮齿动物行为分析方面的专业知识。具体来说，本 R01 将解决以下科学问题：1）关节内的新陈代谢如何改变？ IDO 融合蛋白的关节递送？ 2) 关节内免疫系统的局部调节如何？关节内注射 IDO 融合蛋白会改变吗？ 3) IDO 诱导的代谢变化是否会影响其他因素？ 4) 关节内注射 IDO 融合蛋白能否阻止创伤后 OA 的发作？内侧半月板损伤后？5) 关节内递送 IDO 融合蛋白能否逆转 OA 相关的疾病？疼痛和残疾，即使是在无法修复的关节损伤的情况下，回答这些问题也很重要？用于了解 IDO 融合蛋白的转化风险，以及改进代谢重编程未来 OA 治疗策略。