One of the key substances known to be involved in the biochemical degradation associated with rheumatoid arthritis is interleukin-1 (IL-1). IL-1 is commonly referred to as a cytokine or biological response modifier, because it modulates communication among many different types of cells within the body, including immune cells and bone cells. IL-1 causes thickening of the joint lining (synovium), joint erosion and infiltration of a joint with immune cells that inflame nearby tissues. These processes lead to the eventual breakdown of joint cartilage.

Joints of individuals with rheumatoid arthritis -- the most common, destructive, inflammatory form of arthritis -- have high levels of IL-1. Observations made by the UPMC investigators and others support other clinical and research findings indicating that IL-1 is responsible, in large part, for the painful and disabling consequences of this disease. Blocking the activity of IL-1 may reduce or halt altogether the pain in, and the currently irreversible destruction of, a rheumatoid joint.

By 1989, Dr. Evans and Dr. Robbins, an expert in gene therapy, planned to execute a full-scale research program that would culminate in the world's first clinical gene therapy for arthritis. Preventing IL-1 from damaging joints appeared to be a promising approach. They based their strategy on research showing that synovial cells had receptors on their surfaces for IL-1. They reasoned that if they could block these receptors, they might be able to block tissue destruction initiated by IL-1. They decided to develop a novel therapy incorporating a gene into synoviocytes, which would cause the production of such a blocking protein, IL-1Ra (interleukin-1 receptor antagonist). Once made, IL-1Ra would block IL-1 from binding to these surface receptors and thus interrupt joint inflammation and destruction.

Before testing this treatment in humans could begin, however, the researchers needed to develop a system for delivering the gene to the joint. One aspect of their work was choosing a vector (gene delivery vehicle). The researchers chose to use a replication-defective retrovirus for the vector. This virus cannot multiply in tissues and poses no such threat once introduced into the body. Furthermore, a retrovirus is highly effective in entering synovial cells and producing IL-1Ra for an extended period.

The investigators also needed to choose whether to inject the vector/gene directly into the joint -- direct therapy -- or expose surgically removed synovial cells to the vector/gene -- indirect therapy. This would be done by first removing the synovial cells from a joint, infecting them with the vector/gene in a laboratory and then putting these cells back into an affected joint. There, they would continue to synthesize the IL-1 blocker. The researchers chose to use indirect gene therapy because it currently is safer. Moreover, when this approach is used, the IL-1Ra protein is produced for a longer time within a treated joint (see illustration).

Testing in rabbits proved that this indirect therapy was highly effective in treating a model of rheumatoid arthritis. Drs. Evans and Robbins removed synovial cells that lined the knee joints of anesthetized rabbits. These cells were infected by the retrovirus carrying the human IL-1Ra gene. Then, these modified cells were injected into the knees of normal rabbits, permitting the local production of the IL-1Ra protein. When the researchers injected IL-1 into the knees of these rabbits, the IL-1Ra significantly reduced inflammation and strongly protected articular cartilage within these joints. In control studies, rabbits without the IL-1Ra gene that were injected with IL-1 developed inflammation and cartilage breakdown. This work, along with their additional research using a rabbit model of rheumatoid arthritis known as antigen-induced arthritis, has provided the basis for a gene therapy study in people with rheumatoid arthritis.

The goals of this pilot study include determining whether gene transfer is safe, feasible and well tolerated in humans; whether it leads to expression of the transferred gene within the joint; and whether there is evidence of an appropriate biological response.

In April of 1994, this research protocol was cleared by the UPMC's Institutional Review Board. By the summer of 1995, it received approval from the Recombinant DNA Advisory Committee of the National Institutes of Health, the panel that approves any government funded gene therapy clinical protocol. The protocol received approval from the Food and Drug Administration in January 1996, and the first patient was recruited to the study in March. On April 4, James Herndon, M.D., chairman of the UPMC's department of Orthopaedic Surgery, performed a routine operation to repair an arthritically damaged thumb joint, and some of the patient's synovial cells were removed.

These cells were divided into two tissue cultures -- one that received the IL-1Ra gene and one that did not. On July 17, 1996, after six weeks of outside testing to ensure their safety, the IL-1Ra transformed synovial cells were injected by Dr. Herndon into two of the patient's hand joints. Two of the joints received the control synovial cells. Neither the patient nor the surgeon knew which joints received the manipulated cell or the control cells. On July 24, the joints will be removed and replaced by artificial joints in a medically necessary operation. The treated and control joints will then undergo testing to determine their response to the gene therapy.

Collaborating investigators whose research findings have been essential to the development of this first clinical gene therapy for arthritis include Simon Watkins, Ph.D., assistant professor of cell biology and physiology and director of the UPMC's Structural Biology Imaging Center; Steve Ghivizzani, Ph.D., a post-doctoral fellow; and Richard Kang, M.D., a resident in orthopaedic surgery.

This fall, the researchers expect to present preliminary results of their findings, in addition to data from another animal model that strongly suggest that their therapeutic approach might also be feasible for osteoarthritis, the most common form of arthritis in the world.

Future gene therapies in arthritis may not be limited to those based on IL-1Ra alone. According to the investigators, combination gene therapy in which two mediators are inhibited should provide an even stronger effect. Drs. Evans and Robbins are also investigating the use of gene therapy to treat other orthopaedic and rheumatologic diseases.