The evolving landscape of gene therapy strategies for the treatment of osteoarthritis

Objectives Significant advances have been made in our understanding of osteoarthritis (OA) pathogenesis; however, no disease-modifying therapies have been identified. This review will summarize the gene therapy landscape, its initial successes for OA, and possible challenges using recent studies and examples of gene therapies in clinical trials. Design This narrative review has three major sections: 1) vector systems for OA gene therapy, 2) current and emerging targets for OA gene therapy, and 3) considerations and future directions. Results Gene therapy is the strategy by which nucleic acids are delivered to treat and reverse disease progression. Specificity and prolonged expression of these nucleic acids are achieved by manipulating promoters, genes, and vector systems. Certain vector systems also allow for the development of combinatorial nucleic acid strategies that can be delivered in a single intraarticular injection – an approach likely required to treat the complexity of OA pathogenesis. Several viral and non-viral vector-based gene therapies are in clinical trials for OA, and many more are being evaluated in the preclinical arena. Conclusions In a post-COVID era, the future of gene therapy for OA is certainly promising; however, the majority of preclinical validation continues to focus heavily on post-traumatic models and changes in only cartilage and subchondral bone. To ensure successful translation, new candidates in the preclinical arena must be examined against all joint tissues as well as pain using diverse models of injury-, obesity-, and age-induced disease. Lastly, consideration must be given to strategies for repeat administration and the cost of treatment owing to the chronic nature of OA.