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

• 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
• 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

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.

项目摘要 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在很大程度上失败了。为了应对这一挑战，我们 该团队正在开发一种创新的代谢重编程策略，用于治疗膝关节OA。在我们的战略中， 吲哚胺2，3-双加氧酶（IDO），一种免疫抑制酶，将被关节内递送至 将色氨酸分解代谢成犬尿氨酸。基于IDO在其他组织中的作用， 代谢可能会驱使关节水平的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， 我们的酶将在OA影响的关节中持续产生抗炎代谢物， 延长抗炎作用，可能重置关节中的免疫稳态。虽然IDO 能持续产生抗炎代谢产物，游离IDO则受到关节清除。为了解决这个 为了应对挑战，我们还将IDO与碳水化合物结合蛋白融合，从而延长IDO的联合停留时间 通过新的组织锚定方法。此外，因为组织锚定的IDO不需要释放到 产生抗炎信号，锚定的IDO将继续产生抗炎犬神经氨酸 而不需要我们的“药物”（IDO）释放和结合特定的目标。我们的初步数据表明， 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延长 酶停留时间从几天到超过4周，以及IDO的关节内递送 融合蛋白可以改变色氨酸代谢，减少炎症，并逆转大鼠的疼痛相关行为 膝关节OA模型。因此，该R 01提案寻求评估IDO融合蛋白的关节内递送， 创伤后控制关节炎症和减少OA相关病理性重塑的治疗策略 (Aim 1）和慢性OA症状发作后（目的2）。为了实现这些目标，我们的团队将整合 在代谢分析、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。 具体而言，本R 01将解决以下科学问题：1）关节内代谢如何改变？ 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 通过关节内注射IDO融合蛋白来改变吗3)IDO诱导的代谢变化是否影响其他 关节组织也是吗4)关节内注射IDO融合蛋白能否延缓创伤后OA的发生 内侧半月板损伤后和，5）IDO融合蛋白的关节内递送是否可以逆转OA相关的 疼痛和残疾，即使是在无法弥补的关节损伤的情况下？回答这些问题很重要 了解我们的IDO融合蛋白的翻译风险，以及改进代谢重编程 未来的治疗策略。