Gene therapy for human osteoarthritis: principles and clinical translation

Introduction: Osteoarthritis (OA) is the most prevalent chronic joint disease. Its key feature is a progressive articular cartilage loss. Gene therapy for OA aims at delivering gene-based therapeutic agents to the osteoarthritic cartilage, resulting in a controlled, site-specific, long-term presence to rebuild the damaged cartilage. Areas covered: An overview is provided of the principles of gene therapy for OA based on a PubMed literature search. Gene transfer to normal and osteoarthritic cartilage in vitro and in animal models in vivo is reviewed. Results from recent clinical gene therapy trials for OA are discussed and placed into perspective. Expert opinion: Recombinant adeno-associated viral (rAAV) vectors enable to directly transfer candidate sequences in human articular chondrocytes in situ, providing a potent tool to modulate the structure of osteoarthritic cartilage. However, few preclinical animal studies in OA models have been performed thus far. Noteworthy, several gene therapy clinical trials have been carried out in patients with end-stage knee OA based on the intraarticular injection of human juvenile allogeneic chondrocytes overexpressing a cDNA encoding transforming growth factor-beta-1 via retroviral vectors. In a recent placebo-controlled randomized trial, clinical scores were improved compared with placebo. These translational results provide sufficient reason to proceed with further clinical testing of gene transfer protocols for the treatment of OA.