Osteoarthritis Gene Therapy: A 30-Year Journey From Concept to Clinical Trials

This manuscript summarizes over 30 years of research that began with the novel concept of using intra-articular gene transfer to treat joint diseases. A notable milestone in this journey was the first-in-human transfer of an exogenous gene to a joint, accomplished by the ex vivo delivery of cDNA encoding the interleukin-1 receptor antagonist (IL-1Ra) to joints of patients with rheumatoid arthritis. Responding to lessons learned from this study and the prevailing clinical landscape we next developed an in vivo gene delivery system based on adeno-associated virus (AAV) with osteoarthritis (OA) as the target disease. The safety and efficacy of this vector, sc-rAAV2.5IL-1Ra, was demonstrated in the joints of rats and horses leading to a successful IND application to the FDA. In this clinical trial (ClinicalTrials. gov Identifier: NCT02790723) sc-rAAV2.5IL-1Ra was injected at escalating doses into the knee joints of nine patients with OA who were followed for 1 year. This trial met its primary outcome measure, safety, and demonstrated that sustained expression of transgenic IL-1Ra was possible after a single injection of the vector. Patient-reported outcomes improved, but without a control group it is not possible to determine the influence of a placebo effect. This and other unresolved matters are addressed in a recently-completed Phase Ib trial (ClinicalTrials. gov Identifier: NCT05835895). Beyond OA, sc-rAAV2.5IL-1Ra has potential therapeutic value in a variety of degenerative, inflammatory, fibrotic and autoimmune conditions. More generally, gene therapy holds much promise in the field of regenerative medicine, including regenerative orthopaedics. Trial Registration: (ClinicalTrials. gov Identifier: NCT02790723, NCT05835895).