Zhou Kaiyi, Yuan Meng, Sun Jiabao, Zhang Feixu, Li Xinting, Xiao Xiao, Wu Xia
School of Pharmacy, East China University of Science and Technology, Shanghai, China.
State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China.
Gene Ther. 2025 Jan 20. doi: 10.1038/s41434-025-00515-y.
Osteoarthritis (OA), a prevalent joint disorder, can lead to disability, with no effective treatment available. Interleukin-1 (IL-1) plays a crucial role in the progression of OA, and its receptor antagonist (IL-1Ra), a natural IL-1 inhibitor, represents a promising therapeutic target by obstructing the IL-1 signaling pathway. This study delivered IL-1Ra via adeno-associated virus (AAV), a gene therapy vector enabling long-term protein expression, to treat knee osteoarthritis (KOA) in animal models. scAAV-oIL-1Ra-I1/2 injected directly into the joint in both MMT/ACLT-induced KOA model rat improved abnormal gait (increasing footprint area and pressure), subchondral bone lesions, and significantly reduced cartilage wear and pathological scores. In the MMT-induced KOA rabbit model, weight-bearing asymmetry (indicating pain) improved after 8 weeks of scAAV-oIL-1Ra-I1/2 administration, and X-ray showed decreased K-L scores (severity grade), reduced cartilage loss, and lower pathology scores compared to untreated animals. Additionally, sex-determining region Y-type high mobility group box 9 (SOX9) was co-delivered with IL-1Ra via AAV in ACLT + MMT-induced KOA rats. The combined treatment significantly alleviated subchondral bone lesions, cartilage destruction, synovial inflammation, and pathological scores, demonstrating superior efficacy compared to either treatment administered alone. Co-delivering IL-1Ra and SOX9 inhibited IL-1 mediated inflammatory signaling, maintained cartilage homeostasis, and promoted its repair in KOA models, suggesting potential for clinical use.
骨关节炎（OA）是一种常见的关节疾病，可导致残疾，目前尚无有效的治疗方法。白细胞介素-1（IL-1）在OA的进展中起关键作用，其受体拮抗剂（IL-1Ra）作为一种天然的IL-1抑制剂，通过阻断IL-1信号通路成为一个有前景的治疗靶点。本研究通过腺相关病毒（AAV，一种能够实现长期蛋白表达的基因治疗载体）递送IL-1Ra，以治疗动物模型中的膝骨关节炎（KOA）。在MMT/ACLT诱导的KOA模型大鼠中，直接向关节内注射scAAV-oIL-1Ra-I1/2可改善异常步态（增加足迹面积和压力）、软骨下骨病变，并显著减少软骨磨损和病理评分。在MMT诱导的KOA兔模型中，给予scAAV-oIL-1Ra-I1/2 8周后，负重不对称（表明疼痛）得到改善，X线显示与未治疗的动物相比，K-L评分（严重程度分级）降低、软骨损失减少且病理评分更低。此外，在ACLT + MMT诱导的KOA大鼠中，通过AAV将性别决定区Y型高迁移率族盒9（SOX9）与IL-1Ra共同递送。联合治疗显著减轻了软骨下骨病变、软骨破坏、滑膜炎症和病理评分，与单独给予任何一种治疗相比，显示出更好的疗效。在KOA模型中，共同递送IL-1Ra和SOX9可抑制IL-1介导的炎症信号传导，维持软骨稳态并促进其修复，表明具有临床应用潜力。
