Key result
Intraarticular gene therapy using an AAV-etanercept vector can likely be accomplished safely, though fundamental issues of transgene expression must be addressed before robust clinical responses can be expected.
Highlights the transition of arthritis gene therapy from preclinical and small Phase I studies to Phase II efficacy trials.
Arthritis has been on the gene therapy agenda for about 20 years1. Despite its impressive preclinical track record of efficacy and safety in animal models (as reviewed5,6), progress in carrying out clinical trials has been painfully slow4. The literature contains only 2 small Phase I studies3,4 and a report of 2 subjects who experienced symptomatic relief following gene transfer7. The Phase I/II trial described by Mease, et al in this issue of The Journal 8 is thus very much to be welcomed. Not only does it greatly increase the number of subjects who have received gene therapy for arthritis, but it is also the first trial to address efficacy in a substantial fashion. Although there are several different strategies for using genes as therapeutic agents in arthritis, by far the most progress has been made with the approach of delivering genes locally to individual diseased joints2,3. There are a number of reasons for this. Not only was it the first arthritis gene therapy strategy to be proposed1, but also, by enabling sustained, endogenous, intraarticular synthesis of therapeutic gene products in selected joints, local delivery achieves something that no other technology can accomplish. Moreover, expressing the gene product intraarticularly minimizes exposure of non-target sites, thereby reducing the potential for unwanted side effects. The smaller requirements of local, rather than systemic, treatment also lower costs, especially as a successful gene therapy will require infrequent redosing. The burden of treating multiple joints individually in patients with rheumatoid arthritis (RA) may be less than first thought, following the discovery that the genetic treatment of just one joint in animals with polyarticular disease secures improvement in additional joints on the same individual9. The degree to … Address correspondence to C. Evans; E-mail: cevans{at}bidmc.harvard.edu
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Christopher H. Evans (2010) conducted an editorial in Rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis (n=120). rAAV2-TNFR:Fc (tgAAC94) vs. Placebo was evaluated on Clinical outcomes including target joint swelling and tenderness. Intraarticular gene therapy using an AAV-etanercept vector can likely be accomplished safely, though fundamental issues of transgene expression must be addressed before robust clinical responses can be expected.
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