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First tests to use gene therapy for rheumatoid arthritis
show it to be safe
By Roberta Friedman

Initial trials using gene therapy for arthritic joints have been successful, researchers reported at a recent meeting of the American Academy of Orthopaedic Surgeons in San Francisco. This first test of gene therapy for a non-lethal disease has shown the technique to be safe, and more prolonged studies of the engineered cells are planned, University of Pittsburgh School of Medicine investigator Paul D. Robbins said. The initial tests showed high levels of expression of therapeutic genes in the patients' synovial cells—the cells that nurture the joint with cushioning fluid, Robbins said. The findings are being prepared for publication.

The gene, which was delivered directly to the patients' finger joints, codes for a interleukin-1 receptor antagonist, a protein that prevents this particular inflammatory mediator from latching onto its cellular target. Amgen, of Thousand Oaks, California, has been testing the protein in patients in whom too many inflammatory agents are released. Due to these tests by Amgen, the Pittsburgh team knew that the toxicity profile of the receptor antagonist appears to be very good, Robbins said, so they colonized the synovial lining with cells bearing the gene for the antagonist.

The patients who were having surgery to replace severely arthritic knuckle joints agreed to have injections of the genetically modified cells to see if the procedure is safe. The joints' diseased knuckles were then surgically removed and examined, and the patients' cells were banked "Some of these patients have now discussed the option of putting the cells back in and allowing them to reside there for extended periods of time," said Robbins. "That is where our Phase II study is going to go," he added, once the US Food and Drug Administration gives approval.

Nine patients were tested with a total of three different doses of cells with the inserted gene: a million, five million and ten million, three patients at each dose. No adverse effects resulted from the gene therapy, and physiologic responses to the boosted gene supply matched the investigators' expectations that interleukin-1 would act as a mediator of inflammation. In cells isolated from the treated joints, the cytokines expected to go down did so, and those expected to increase in response to the supply of the receptor antagonist did so as well.

The joints that were tested were highly diseased, so no therapeutic response was expected, Robbins said. "What this does mean, is that [the therapy] appears to be well tolerated...this was the proof of principle," he added.

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