By Sean Henahan, Access Excellence

PITTSBURGH The first clinical study of gene therapy for people with arthritis is now underway at the University of Pittsburgh. While the test is primarily designed to measure the safety of the procedure, researchers should also get some idea of the therapeutic potential for this approach.

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"This gene therapy is unique. It opens a new chapter for the treatment of arthritis, other autoimmune diseases, and additional disorders of bones and joints. We are optimistic that this type of intervention will someday halt the biological processes underlying these diseases," said Chris Evans, Ph.D., principal investigator for the study, and Professor of Orthopaedic Surgery at the the University of Pittsburgh.

A 68-year-old woman became the first patient ever to receive gene therapy an autoimmune disorder, a disease in whcih the patient's own immune system attacks native tissue. The patient, who has rheumatoid arthritis, received injections of her own cells into the knuckles of one hand. These cells were cultured and modified to carry a gene that blocks both joint erosion and inflammation caused by interleukin-1 (IL-1). IL-1, a biological response modifier, is active in many biological processes within tissues.

The patient's synovial cells were removed from her thumb joint in an operation to stabilize that joint. Some of the synovial cells were cultured and then exposed to the gene, whereas others were grown but did not receive the gene. After testing the cultures for any microbial contaminants, cells were injected into the four knuckle joints on one hand. Two of the joints received injections with gene-containing cells. Two joints received injections of cultured cells without the gene. Neither the patient nor the surgeon knew which knuckles were being treated with the gene.

One week later the patient then underwent surgery to replace her own arthritic joints with artificial ones. She would have needed this procedure irrespective of her participation in this study. The tissues and diseased joints removed during surgery will be evaluated. Preliminary results from this study, which includes nine women, are not anticipated until later this fall.

"We hope that this type of therapy would eventually reduce the amount or complexity of surgery required by many patients with rheumatoid arthritis and other chronic joint disorders," said Dr. Herndon, who added, "We are extremely grateful to the pioneering patients who have already entered this phase I study."

"We have designed an excellent vector, or gene delivery system, for this study," said Paul Robbins, Ph.D., co-principal investigator on the study. "The retrovirus used to carry the therapeutic gene will not reproduce inside the body."

Normally, IL-1 is involved in provoking inflammation to ward off infection or disease. In the case of rheumatoid arthritis, the immune system attacks a person's own tissues in what is called autoimmunity. Once released inside a joint, IL-1 causes both inflammation and erosion of joint tissues, as well as limited mobility and chronic pain associated with rheumatoid arthritis.

The gene being delivered in this protocol makes interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra attaches to receptors on the surface of synovial cells. IL-1 normally binds to these receptors, but IL-1Ra prevents this process from occurring. Rigorous, pre-clinical research by UPMC scientists has shown that IL-1Ra prevents the destructive consequences of IL-1 in animals.

"It is important to inject the genetically manipulated cells into the affected joint. If the blocking agent IL-1Ra were injected into the bloodstream, it might cause severe side effects in other parts of the body that are unaffected by rheumatoid arthritis but which are in some way regulated by IL-1. Moreover, IL-1Ra would break down more easily in the blood, so you would need to deliver much greater quantities of it to reach therapeutic levels in the affected joints," said Dr. Robbins.

"Current therapies reduce pain and inflammation, but they do not stop the progress of rheumatoid arthritis, which this study is designed to address," said James Herndon, M.D., chairman of the UPMC's Department of Orthopaedic Surgery.

For details on the treatment protocol, see the June 20. 1996 issue of Human Gene Therapy (Vol. 7:1261-1280).