Gene therapy pipelines for osteoarthritis: current innovations, operational challenges, and future directions

作者：Valtteri Peitso, Karman Ng, R. Ellis, Jean‐Yves Reginster, Christopher H. Evans, Ali Mobasheri · 发表于：Connective Tissue Research · 年份：2025 · DOI：10.1080/03008207.2025.2520319 · 被引用次数：11 · 研究领域：Osteoarthritis Treatment and Mechanisms、Knee injuries and reconstruction techniques、Inflammatory mediators and NSAID effects

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 refine...