Gene Therapy Combating Inflammation in Arthritis, HF

Gene Therapy Combating Inflammation in Arthritis, HF

ST. LOUIS—For the first time, studies are showing that gene therapy targeting the

inflammatory process typical in advanced rheumatoid arthritis (RA) and other chronic conditions, such as congestive heart failure (CHF), is both feasible and safe, researchers reported at the 8th American Society of Gene Therapy annual meeting. “One of the goals of gene therapy is to

develop it as an off-the-shelf type of medicine. Some of these vectors can be formulated,

stabilized, delivered, and then given [to patients] by intravenous injection,” said Donald Kohn, MD, director, Gene Therapy Program, Children’s Hospital Los Angeles School of dicine/University of Southern California. In RA, macrophages and lymphocytes colonize the lining of joints and release cytokines that modulate communication between immune cells and synovial cells. Over the past 10 years, investigators have discovered that synovial cells have a receptor on their surface that is a perfect fit for a particular cytokine, interleukin 1 (IL-1). When IL-1 binds

to this receptor, it triggers the cell to unleash additional biochemical agents. This, in turn, produces further local inflammation, which causes progressively worse pain and stiffness in

the affected joints. Investigators at the University of Pittsburgh School of Medicine were uccessful in blocking this process in a study of 9 women (aged 49-73 years) who

had been living with RA for >10 years (range, 10-26 years) by injecting a gene

that encodes the IL-1 receptor antagonist (Ra) into affected joints. Each patient was scheduled for joint replacement surgery involving 4 knuckles on 1 hand and 1 additional joint. In the

weeks before the surgery, synovial tissue was removed from the additional joint that required surgery. Cells from the tissue were then cultured for several weeks, after which one half of the cells had the IL-1 Ra gene inserted. Patients returned to the clinic 6 weeks later, and the cells were injected into 4 knuckles in a double-blind fashion; 2 knuckles received the gene-modified cells, and 2 knuckles received injections of cells with no added gene. One week later, at the time of the patient’s previously scheduled surgery, the 4 knuckles were removed for study and replaced with artificial joints. Joints treated with the genetically modified cells exhibited high levels of IL-1 Ra, indicating successful gene transfer. Clusters of cells that expressed large amounts of the gene were also found at the surface of the synovial tissue and produced significantly

less inflammation-provoking IL-6. The researchers say their results show that successful

gene transfer can target joint inflammation, thereby opening the door for gene-based therapies to fight inflammation in RA and osteoarthritis. “This is an important first step forward in the attempt to arrest arthritis,” said Savio Woo, PhD, director, Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York City. Similarly, in the treatment of severe

CHF, data from human clinical trials suggest it may be possible to deliver new gene

products into coronary arteries. Over the next 12 to 18 months, several phase 2 trials are expected to investigate the ability of gene therapy to treat severe CHF.

Worldwide, it is estimated that about 920 clinical trials involving gene therapy

are under way; >65% of them are