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

通过靶向 IL-27 声波传递促进关节炎的内源性骨修复

• 批准号: 10352199
• 负责人: Marxa L Figueiredo
• 金额: $ 33.51万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-16 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352199
• 关键词: Affect; Anti-Inflammatory Agents; Antibodies; Arthritis; Articulation; Binding; Biological Products; Biological Response Modifiers; Bone Matrix; Cell Communication; Cells; Collagen Arthritis; Collagen Type II; Data; Equilibrium; Gene Delivery; Goals; Growth Factor; Homeostasis; Immune; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-17; Interleukins; Intervention; Joints; Ligands; Maintenance; Mediating; Medical; Methods; Modeling; Monoclonal Antibodies; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteogenesis; Pain; Patients; Plasmids; Polymers; Population; Positioning Attribute; Quality of life; Recombinant Interleukins; Recombinants; Rheumatoid Arthritis; Risk; STAT1 gene; STAT3 gene; Signal Transduction; Specificity; Synovial Cell; Synovitis; System; TNF gene; TNFSF11 gene; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; bone; bone cell; bone erosion; bone healing; bone loss; bone repair; collagen antibody induced arthritis; cytokine; fracture risk; gene delivery system; improved; inflammatory bone loss; macrophage; monocyte; novel; novel therapeutics; osteoblast differentiation; osteoblast proliferation; osteoclastogenesis; pain relief; plasmid DNA; receptor; repaired; restoration; sonoporation; subcutaneous; virtual

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.

项目总结 改善对滑膜炎症的控制可减缓骨侵蚀并降低 骨折和疼痛。然而，即使是有效的抗炎策略，如阻断肿瘤坏死因子或白介素6受体，仅 显示有限的骨修复，表明抑制炎症不足以恢复骨免疫 平衡。一些当前和新兴的疗法通过抑制破骨细胞的活动成功地减缓了侵蚀， 但不能显著刺激骨形成。此外，这些生物制品的目标不是积累在 关节发炎，因此全身给药，增加了严重感染的可能性。为 治疗要成功地促进骨骼修复，他们可能必须平衡几个水平和活动 前炎性细胞破坏它们与破骨细胞的相互作用，促进成骨细胞成熟或活动。 因此，对炎症性骨丢失的一个严重的未得到满足的需求是一种干预措施，它可以通过 重新平衡免疫：骨骼细胞动态平衡，以降低骨折风险，提高患者的生活质量 病人。最近的数据表明，细胞因子白介素27(IL-27)作为免疫和免疫调节因子的新用途 骨骼细胞平衡，因为它减少了破骨细胞的生成，促进了成骨细胞的增殖和成熟。 此外，IL-27还抑制免疫细胞和滑膜细胞的活性，这些细胞介导了糖尿病的发生和维持。 此外，它还具有抗血管生成活性。目前提供重组(R)IL-27的策略是 全身性的，缺乏免疫或骨细胞的特异性，而且无法维持治疗效果 随着时间的推移，由于快速清关。我们建议研究靶向IL-27是否通过使用 持续表达系统，将有效地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。关节腔内声学修复基因传递 (SonoDelivery)将把编码靶向IL-27的聚合物和质粒DNA的纳米复合体转移到关节 消炎促进骨修复。我们的假设是优化IL-27的传递和靶向 通过重新平衡骨免疫动态平衡，促进内源性骨修复。 为了验证这一假设，我们建议1)为了达到关节中细胞因子的治疗水平，我们将优化 IL-27关节内超声传递；2)增强细胞因子在骨中的滞留，促进内源性骨 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)增强细胞因子 保留在血管疙瘩和滑膜衬里，促进骨修复，我们将促进配体介导的靶向 IL-27对炎症细胞和免疫细胞的作用。我们预计，这种简单的声音传递策略将提供 修复受类风湿性关节炎(RA)影响的关节中受侵蚀的骨的有效方法。IL-27是独一无二的 它能够同时抑制炎症和促进骨骼修复。这种方法令人兴奋，因为我们 设想在以骨质流失为特征的多种条件下的应用。

项目成果

Fluorinated Polymer Zwitterions: Choline Phosphates and Phosphorylcholines.

• DOI: 10.1021/acsmacrolett.1c00451
• 发表时间: 2021-09
• 期刊: ACS macro letters
• 影响因子: 5.8
• 作者: Le Zhou;Alexandria Triozzi;M. Figueiredo;T. Emrick

Polymer-mediated gene therapy: Recent advances and merging of delivery techniques.

• DOI: 10.1002/wnan.1598
• 发表时间: 2020-03
• 期刊: Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
• 作者: Salameh JW;Zhou L;Ward SM;Santa Chalarca CF;Emrick T;Figueiredo ML
• 通讯作者: Figueiredo ML

Editorial: IL-27 expression following TLR activation in bone: sounding the alarm for repair.

社论：骨中 TLR 激活后 IL-27 的表达：敲响修复警报。

• DOI: 10.1189/jlb.3ce1016-442rr
• 发表时间: 2017
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Figueiredo,MarxaL

Combination of Interleukin-27 and MicroRNA for Enhancing Expression of Anti-Inflammatory and Proosteogenic Genes.

• DOI: 10.1155/2017/6365857
• 发表时间: 2017
• 期刊: Arthritis
• 作者: Figueiredo Neto M;Figueiredo ML
• 通讯作者: Figueiredo ML

Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling.

• DOI: 10.3390/cancers14133039
• 发表时间: 2022-06-21
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Sun, Xun;Li, Ke-Xin;Figueiredo, Marxa L.;Lin, Chien-Chi;Li, Bai-Yan;Yokota, Hiroki
• 通讯作者: Yokota, Hiroki