Facilitating Endogenous Bone Repair in Arthritis with Targeted IL-27 Sonodelivery

项目摘要 改善对滑膜炎症的控制，预计将减缓骨质侵蚀，降低骨关节炎的风险。 骨折和疼痛。然而，即使是有效的抗炎策略，如阻断TNF或IL 6 R， 显示有限的骨修复，表明抑制炎症不足以恢复骨免疫， 平衡一些目前和新兴的疗法通过抑制破骨细胞活性成功地减缓了侵蚀， 但不能显著刺激骨形成。此外，这些生物制剂不以累积为目标， 发炎的关节，因此全身给药，增加了严重感染的可能性。为 为了成功地促进骨修复，它们可能必须平衡几种骨修复剂的水平和活性。 促炎细胞破坏它们与破骨细胞的相互作用，并促进成骨细胞成熟或活性。 因此，炎性骨丢失的关键未满足需求是可以通过以下方式恢复侵蚀骨的干预： 重新平衡免疫：骨细胞稳态，以降低骨折风险，提高生活质量， 患者最近的数据指出了细胞因子白细胞介素-27（IL-27）作为免疫调节剂的新用途， 骨细胞平衡，因为它减少破骨细胞生成并促进成骨细胞增殖和成熟。 此外，IL-27抑制免疫和滑膜细胞的活性，这些细胞介导炎症的发生和维持。 并且还具有抗血管生成活性。目前用于递送重组（r）IL-27的策略是 全身性，对免疫细胞或骨细胞缺乏特异性，而且不能维持治疗效果 随着时间的推移，由于快速清除。我们建议检查是否有针对性的IL-27，使用 持续表达系统，将有效促进骨修复和减少关节炎症 使用胶原抗体诱导的关节炎（CAIA）模型。关节腔内声致穿孔基因传递 （超声递送）将聚合物和编码靶向IL-27的质粒DNA的纳米复合物转移到关节中， 减少炎症和促进骨修复。我们的假设是，优化IL-27的递送和靶向 对关节的作用将通过重新平衡骨免疫稳态来促进内源性骨修复。 为了验证这一假设，我们提出：1）为了达到关节中细胞因子的治疗水平，我们将优化 IL-27关节内超声递送; 2）增强细胞因子在骨中的保留并促进内源性骨形成 修复，我们将促进配体介导的IL-27靶向骨细胞或基质，以及3）为了增强细胞因子 保留在血管翳和滑膜衬里，促进骨修复，我们将促进配体介导的靶向 IL-27对炎症和免疫细胞的作用。我们预计，这种简单的声传递策略将提供一种 有效的手段来恢复侵蚀骨关节类风湿关节炎（RA）的影响。IL-27是唯一的 它能够同时抑制炎症并促进骨修复。这种方法令人兴奋，因为我们 设想应用于以骨丢失为特征的多种病症。

PROJECT SUMMARY Improved control over synovial inflammation is anticiapted to slow bone erosion and reduce the risk of fractures and pain. However, even potent anti-inflammatory strategies such as blockade of TNF or IL6R, only show limited bone repair, suggesting that suppressing inflammation is insufficient to restore osteo-immune balance. Some current and emerging therapies succeed in slowing erosion by suppressing osteoclast activity, but fail to significantly stimulate bone formation. Further, these biologics are not targeted for accumulation at inflammed joints, thus are administered systemically, enhancing the likelihood of serious infection. For therapeutics to succeed in promoting bone repair, they likely must balance levels and activity of several proinflammatory cells to disrupt their interaction with osteoclasts, and promote osteoblast maturation or activity. Thus a critical unmet need for inflammatory bone loss is an intervention that can restore eroded bone through rebalancing immune:bone cell homeostasis in order to reduce fracture risk and improve quality of life for patients. Recent data points to a novel use for cytokine Interleukin-27 (IL-27) as a regulator of immune and bone cell balance, as it reduces osteoclastogenesis and promotes osteoblast proliferation and maturation. Also, IL-27 suppresses activities of immune and synovial cells mediating the onset and maintenance of inflammation and also has anti-angiogenic activity. Current strategies for delivering recombinant (r)IL-27 are systemic and lack specificity to immune or bone cells, and moreover are unable to sustain therapeutic effects over time due to rapid clearance. We propose to examine whether a targeted IL-27, delivered using a sustained expression system, will be effective in promoting bone repair and reducing inflammation in joints using a collagen-antibody induced arthritis (CAIA) model. Intraarticular sonoporation gene delivery (sonodelivery) will transfer into the joints a nanoplex of polymer and plasmid DNA encoding targeted IL-27 to reduce inflammation and promote bone repair. Our hypothesis is that optimizing delivery and targeting of IL-27 to joints will facilitate endogenous bone repair by re-balancing osteo-immune homeostasis. To test this hypothesis, we propose 1) To achieve therapeutic levels of cytokine in joints, we will optimize IL-27 intra-articular sonodelivery; 2) To enhance cytokine retention in bone and promote endogenous bone repair, we will promote ligand-mediated targeting of IL-27 to bone cells or matrix, and 3) To enhance cytokine retention at the pannus and synovial lining and facilitate bone repair, we will promote ligand-mediated targeting of IL-27 to inflammatory and immune cells. We anticipate that this simple sonodelivery strategy will provide an efficient means to restore eroded bone in articulations affected by rheumatoid arthritis (RA). IL-27 is unique in its ability to simultaneously inhibit inflammation and promote bone repair. This approach is exciting in that we envision applications across numerous conditions characterized by bone loss.