McGowan Institute for Regenerative Medicine
faculty members Paul Robbins, PhD (top), and Theresa Whiteside, PhD (bottom), were members of a research team that has reported the first clinical evidence that gene therapy reduces symptoms in patients with rheumatoid arthritis (RA), an important milestone for this promising treatment. Originally conceived as a means of treating genetic diseases, such as cystic fibrosis and hemophilia, gene therapy involves implanting a normal gene to compensate for a defective gene in the patient. The first clinical trial to test gene therapy was launched in 1990 for the treatment of a rare, genetic immunodeficiency disease.
A classic autoimmune disease, RA develops when, for unknown reasons, the body’s immune system turns against itself, causing joints to become swollen and inflamed. If the disease is inadequately controlled, the tissues of the joint are eventually destroyed. Although anti-inflammatory agents and biologics can help to mitigate symptoms, there is no cure for the condition, estimated to affect more than 2 million individuals in the U.S. alone. Not all patients respond well to current treatment options which are expensive, must be administered regularly, and have potentially risky side effects.
The study’s principal investigator is Christopher Evans, PhD, Director of the Center for Advanced Orthopaedic Studies at Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. Dr. Evans has spent many years studying the molecules responsible for the breakdown of cartilage in patients with arthritis, identifying interleukin-1 as a good target for the gene therapy. By implanting a gene in the affected joint, he and his team were able to stimulate production of a human interleukin-1 receptor antagonist protein, which serves to block actions of the interleukin-1 protein.
“The idea is that by remaining in place, the new gene can continuously block the action of the interleukin-1 within the joints,” says Dr. Evans. “In essence, the gene becomes its own little factory, continuously working to alleviate pain and swelling.”
This study, conducted in Germany, was to prove that the therapy was not only safe, but that it was of therapeutic benefit. Two study subjects were recruited. Both subjects were postmenopausal females under the age of 75 with a diagnosis of advanced RA. After tissue was removed from the subjects’ knuckle joints, a harmless retrovirus was inserted into the tissue cells, in order to serve as a “vector” to transport the gene into the patients’ joints. After being placed in culture to grow and replicate, the cells were injected back into the afflicted joints.
After 4 weeks, patients reported reduced pain and swelling. It was reported that one of the patients experienced dramatic effects—the gene-treated joints remained pain-free even though other joints flared. Subsequent laboratory tests showed that tissues removed from the subject’s joint tissue synthesized lower amounts of disease-related proteins, confirming that the reduction in pain and swelling resulted from the actions of the implanted gene. This is the first real evidence that the painful symptoms of RA can indeed be lessened through gene therapy.
Dr. Robbins is a Professor of Molecular Genetics and Biochemistry at the University of Pittsburgh School of Medicine. Dr. Whiteside is the Director of the Immunologic Monitoring and Cellular Products Laboratory at the University of Pittsburgh Cancer Institute, and a Professor of Pathology, Otolaryngology, and Immunology at the University of Pittsburgh.
Illustration: McGowan Institute for Regenerative Medicine.
Beth Israel Deaconess Medical Center Press Release (01/26/09)
Science Daily (01/27/09)
Bio: Dr. Paul Robbins
Bio: Dr. Theresa Whiteside
Abstract (Human Gene Therapy. February 1, 2009, 20(2): 97-101)