Peitso Valtteri, Ng Karman, Ellis Ron, Reginster Jean-Yves, Evans Christopher H, Mobasheri Ali
Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland.
KNG Consulting LLC, Livingston, NJ, USA.
Connect Tissue Res. 2025 Jul 4:1-8. doi: 10.1080/03008207.2025.2520319.
Osteoarthritis (OA) is a multifactorial joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. Despite its significant global health burden, there are currently no disease-modifying pharmacological therapies for OA. Gene therapy, leveraging viral and non-viral vectors to deliver therapeutic transgenes into the joint environment, shows significant promise.
This mini-review highlights recent innovations in OA gene therapy pipelines, focusing on Platforms employing recombinant adenovirus, adeno-associated virus (AAV), and herpes simplex virus vectors. Strategies include AAV-mediated delivery of interleukin-1 receptor antagonist (IL-1Ra) and truncated nkx3.2 transcription factor to modulate inflammation and promote chondrocyte survival. Non-viral approaches, such as plasmid DNA encoding interleukin-10, are also under investigation.
Emerging data from preclinical and clinical studies demonstrate the feasibility of achieving sustained, intra-articular transgene expression with therapeutic efficacy in animal models and early-phase human trials. However, challenges persist, including immune barriers to repeat dosing, variability in vector performance, and the high costs of treatment. Additionally, agerelated declines in transduction efficiency, the heterogeneity of OA, and systemic metabolic influences complicate therapeutic outcomes.
To overcome current regulatory obstacles, future research must prioritize the refinement of vector systems to enhance safety, potency, and specificity, as well as the development of combination therapies integrating genetic and conventional approaches, targeting pain and improving function. Gene therapy has transformative potential for improving OA management and an important priority is multidisciplinary collaboration to translate preclinical innovations into accessible, effective treatments for a highly heterogeneous and aging patient population.
骨关节炎（OA）是一种多因素关节疾病，其特征为软骨进行性降解、滑膜炎症和软骨下骨重塑。尽管它在全球造成了重大的健康负担，但目前尚无用于OA的疾病修饰药物疗法。基因疗法利用病毒和非病毒载体将治疗性转基因递送至关节环境，显示出巨大的潜力。
本综述重点介绍了OA基因治疗流程中的最新创新，重点关注采用重组腺病毒、腺相关病毒（AAV）和单纯疱疹病毒载体的平台。策略包括AAV介导的白细胞介素-1受体拮抗剂（IL-1Ra）和截短的nkx3.2转录因子的递送，以调节炎症并促进软骨细胞存活。非病毒方法，如编码白细胞介素-10的质粒DNA，也在研究中。
临床前和临床研究的新数据表明，在动物模型和早期人体试验中实现持续的关节内转基因表达并具有治疗效果是可行的。然而，挑战依然存在，包括重复给药的免疫障碍、载体性能的变异性以及治疗成本高昂。此外，转导效率的年龄相关下降、OA的异质性以及全身代谢影响使治疗结果复杂化。
为克服当前的监管障碍，未来的研究必须优先改进载体系统，以提高安全性、效力和特异性，以及开发整合基因和传统方法的联合疗法，以减轻疼痛并改善功能。基因疗法在改善OA管理方面具有变革潜力，一个重要的优先事项是开展多学科合作，将临床前创新转化为针对高度异质性和老龄化患者群体的可及、有效的治疗方法。
