Navigating the Hurdles of Intra-articular AAV Gene Therapy

Joint diseases represent a significant health burden due to their high prevalence and morbidity, yet current treatments fail to provide comprehensive and long-term relief for all patients. In this context, adeno-associated virus (AAV) gene therapy, emerges as a promising approach, offering advantages such as prolonged efficacy and minimal im-munogenicity. AAV has been extensively studied for various medical conditions, with some applications successfully implemented in patient treatments. Currently, there are a few clinical trials utilizing AAV that have been completed for treating arthritis. However, challenges such as transduction efficiency, off-targets, and pre-existing immune response persist. This review provides an overview of the current paradigms of treatment with regards to joint disease, elaborates on the AAV delivery barriers related to application in treating joint diseases, and discusses strategies to improve gene therapy efficacy, in-cluding AAV capsid engineering, small molecular-assisted AAV delivery, optimizing tissue-specific or inflammation-inducible promoters, as well as strategies to mitigate immune responses to AAV.