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Advances and challenges in gene‐based approaches for osteoarthritis

Osteoarthritis (OA), a paramount cause of physical disability for which there is no definitive cure, is mainly characterized by the gradual loss of the articular cartilage. Current nonsurgical and reconstructive surgical therapies have not met success in reversing the OA phenotype so far. Gene transfer approaches allow for a long‐term and site‐specific presence of a therapeutic agent to re‐equilibrate the metabolic balance in OA cartilage and may consequently be suited to treat this slow and irreversible disorder. The distinct stages of OA need to be respected in individual gene therapy strategies. In this context, molecular therapy appears to be most effective for early OA. A critical step forward has been made by directly transferring candidate sequences into human articular chondrocytes embedded within their native extracellular matrix via recombinant adeno‐associated viral vectors. Although extensive studies in vitro attest to a growing interest in this approach, data from animal models of OA are sparse. A phase I dose‐escalating trial was recently performed in patients with advanced knee OA to examine the safety and activity of chondrocytes modified to produce the transforming growth factor β1 via intra‐articular injection, showing a dose‐dependent trend toward efficacy. Proof‐of‐concept studies in patients prior to undergoing total knee replacement may be privileged in the future to identify the best mode of translating this approach to clinical application, followed by randomized controlled trials. Copyright © 2013 John Wiley & Sons, Ltd.