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​UPMC Researchers Present Preliminary Evidence Demonstrating Gene Expression in World's First Arthritis Gene Therapy Patient

SAN FRANCISCO, February 11, 1997 — Results of several tests indicate the successful transfer and expression of a therapeutic gene in the world's first arthritis gene therapy patient, according to a presentation today by a research team from the University of Pittsburgh Medical Center (UPMC) at the annual meeting of the American Academy of Orthopaedic Surgeons in San Francisco. "Our results indicate that we can successfully detect expression of the gene within one week of delivering genetically modified cells to a patient with rheumatoid arthritis," said Richard Kang, M.D., presenter of the research findings, a co-investigator on the study and a resident in the UPMC's department of orthopaedic surgery.

"We are hopeful that this is the first in a series of treated patients who express the gene, underscoring the potential utility of this approach in treating rheumatoid arthritis," said Chris Evans, Ph.D., principal investigator for the study, director of the Ferguson Laboratory for Orthopaedic Research and Henry J. Mankin Professor of Orthopaedic Surgery.

This early-phase study is evaluating the use of a gene for an anti-arthritic protein in patients with rheumatoid arthritis (RA), a common, crippling disease for which there is no cure and few useful treatments. This study is the first to explore gene therapy for an autoimmune disease and marks the transition of gene therapy investigations from their use in fatal diseases such as AIDS or cancer to chronic disorders.

UPMC researchers designed the arthritis gene therapy trial because delivering anti-arthritic proteins to patients with RA is difficult. "We theorized that after we delivered the genes that encode anti-arthritic proteins to a patient's joint, that joint could locally produce its own medicine," said Paul Robbins, Ph.D., associate professor of molecular genetics and biochemistry and co-principal investigator on the study.

Drs. Evans and Robbins first demonstrated the feasibility of this approach in rabbits with arthritis. In this model, a gene for an anti-arthritic protein was successfully transferred and expressed. Moreover, they found that rabbits benefitted therapeutically.

The investigators focused on the gene for interleukin-1 receptor antagonist (IL-1Ra), a safe, naturally occurring protein that blocks the actions of another protein, interleukin-1 (IL-1), which is involved in the production of joint inflammation and destruction associated with arthritis.

The first patient's tissues have undergone several qualitative analyses, including polymerase chain reaction, which indicated that the introduced genetic material, or DNA, was transcribed into RNA, the template from which the IL1-Ra protein is made. Researchers also performed in situ hybridization, which detects IL1-Ra RNA in the tissues. They discovered that the gene was successfully incorporated and expressed in synovial cells within gene-treated joints.

In the clinical study, each patient initially undergoes a medically necessary joint surgery on an affected hand, at which time synovial cells (cells lining the joints) are collected by the researchers. In the laboratory, some of these synovial cells receive a disabled retrovirus containing the gene for IL-Ra. Another batch of cells does not receive the gene. After they have been cultured and have received extensive safety testing, the cells are injected into the four knuckle joints of the patient's previously treated hand. Two of the knuckle joints receive cells carrying the IL1-Ra gene, and the other two knuckle joints receive cells lacking the gene. After one week, the patient receives artificial joint replacements in another medically necessary operation. Knuckles and joint fluid are removed at that time and examined for evidence of gene transfer and expression.

The protocol is designed primarily to test the safety and tolerance of arthritis gene therapy. The introduced gene is not intended to benefit the patient therapeutically. The first patient, a 68-year-old woman treated last July, tolerated the gene transfer and all surgeries well, according to the investigators. Three additional participants have been added to the study, which is expected to recruit a total of nine patients, all of whom are post-menopausal women under age 75.


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