Arthritis Gene Therapy: A Brief History and Perspective

Arthritis gene therapy has its origins in research conducted at the University of Pittsburgh in the late 1980s. This was based on the concept of using gene transfer to intra-articular tissues as a means of locally delivering therapeutic gene products to diseased joints in a sustained and safe manner. This approach has stood the test of time, largely because there is still no other clinically acceptable way to deliver proteins locally to joints in a sustained fashion. Rheumatoid arthritis (RA) and osteoarthritis (OA) have been targeted in this fashion. Preclinical studies in various different species have demonstrated the ability to transfer therapeutic genes to joints safely, express them for extended periods of time, and confer a therapeutic effect in animal models of arthritis. Recent studies using an equine model have resoundingly confirmed this in large joints of human proportions. Because the arthritides are heterogeneous, non-Mendelian disorders with complex, incompletely understood etiopathophysiologies, there are no universally accepted therapeutic gene products. However, cDNAs encoding interleukin-1 receptor antagonist (IL-1Ra) and etanercept have been taken into clinical trials for RA, and transforming growth factor-β₁ (TGF-β₁) cDNA has been used in trials of OA. Additional trials in an advanced preclinical stage of development propose to use interferon-β in subjects with RA and IL-1Ra in subjects with OA. Both of these will use in vivo gene delivery with adeno-associated virus as the vector. A Phase III trial delivering TGF-β₁ in an ex vivo fashion with allogeneic chondrocytes is in advanced planning. Four companies are now engaged in commercializing arthritis gene therapy, indicating further progress in its clinical development. Unresolved scientific issues include characterizing the nature and significance of immune response to vectors, determining the level and duration of transgene expression needed in a particular clinical setting, and identifying clear therapeutic targets. Cost may become an issue as arthritis gene therapy moves into clinical use.