University of Pittsburgh Medical Center researchers have tested the use of gene therapy to arrest the progress of rheumatoid arthritis. It was the first time gene therapy had been used for a chronic disease that was not life-threatening. Most gene therapy applications approved for use in humans have been for the treatment of cancer.
Christopher H. Evans, PhD, working with Paul D. Robbins, PhD, developed the procedure over a six-year period. Evans, the Henry J. Mankin professor of orthopaedic surgery and a professor of molecular genetics and biochemistry at University of Pittsburgh Medical Center, previously had studied the inflammatory reaction caused by the wear particles of joint implants. He turned his attention to developing a gene delivery mechanism that uses a retrovirus to carry a gene that would block the effect of Interleukin-1. Interleukin-1 plays a major role in stimulating the body's immune system response and causes inflammation and destruction of the synovial tissue in joints.
Robbins is associate professor of molecular genetics and biochemistry at the medical center, and director of the center's Viral Vector Core Facility. He previously developed a retrovirus which Evans and Robbins used to carry a gene that prevents receptors in the synovial lining from attaching to Interleukin-1.
The gene delivery system and retrovirus were tested in laboratory rabbits, with additional safety-testing in mice.
In 1994, the Recombinant DNA Advisory Committee of the National Institutes of Health gave provisional approval to the first trial in humans. Full approval came a year later. In January of this year, the Food and Drug Administration gave approval for a test, stipulating that it must be done on postmenopausal women who would have required surgery on joints affected by rheumatoid arthritis.
The trials were started in July by James H. Herndon, MD, chief of orthopaedic surgery at the medical center, and coinvestigator. A 68-year-old woman with severe rheumatoid arthritis in the knuckles of her hands volunteered to be the first of nine patients in the trial. She was scheduled to have her knuckles replaced with artificial knuckles.
Synovial cells were removed from the affected joints and grown in a culture. The virus, which was treated so that it could not reproduce in the body, inserted the gene into the cells. The treated cells were then injected into the affected joints where, researchers hope, they will produce a chemical that prevents the action of Interleukin-1 on the synovial lining.
Dr. Herndon injected the cultured cells into two knuckles and control cells that did not contain the gene into two other knuckles.
In late September, Dr. Herndon said the researchers had identified the gene in the treated cells and the gross inflamation was decreased.
"The new technologies of gene therapy and tissue regeneration are exciting," Dr. Herndon said.
Evans said that if the trials are successful, the researchers will want to start intervening earlier in the disease process and save the joints.
Other uses for gene therapy might be osteoarthritis, osteoporosis, osteogenesis imperfecta and nonunion of bone.
James H. Herndon, MD begins gene therapy procedure.
James H. Herndon, MD, chairman of orthopaedic surgery, University of Pittsburgh Medical Center, and coinvestigator of an arthritis gene therapy study, right, injects genetically manipulated synovial cells into arthritic knuckles of patient. Watching the procedure are Paul Robbins, PhD, associate professor of molecular genetics and biochemistry, coinvestigator, left; Christopher H. Evans, PhD, professor of orthopaedic surgery, coinvestigator; center; and Thomas Muzzonigro, MD, resident, right.