Naturally occurring protein IRAP protects cartilage from damage

by Kenneth L. Marcella, D.V.M.

ARTHRITIS has been affecting horses for as long as there have been horses. Fossilized remains of early equines show the unmistakable bony changes and joint degeneration seen with osteoarthritis. Yet our collective knowledge and understanding of this problem in horses began much more recently.

Equine arthritis was first reported in 1938, but there was little attention to the clinical signs or clinical significance of this condition for the next 25 years. A lecture on osteoarthritis was not presented at the American Association of Equine Practitioners convention until 1966, and the concept of "use trauma," or wear-and-tear degeneration of joints, was just beginning to be accepted by the '70s.

Use of arthroscopy first was reported in the horse in 1975, and soon an explosion of research and study into the causes, complications, treatment, and prevention of osteoarthritis followed. To say that veterinarians and scientists have come a long way in a short time is an understatement, and the most recent arrival of various gene therapies for the prevention of joint degeneration marks the beginning of yet another era in the history of equine arthritis.

Treatment goals

Earlier methods of treating arthritis were directed at lessening the pain of the condition but unfortunately did little to stop the damage or reverse the process. The development of products such as glucosamines and chondroitins represented a significant step toward actually repairing defects in joint surfaces. Use of intra-articular injections of various products such as sodium hyaluronate and corticosteroids took joint-health maintenance to yet another level. Wayne McIlwraith, B.V.Sc., Ph.D., a leading scientist and veterinary surgeon at the Orthopedic Research Center at Colorado State University, said the goal of joint therapy soon became "to return the joint to typical as soon as possible and to prevent the recurrence or reduce the severity of osteoarthritis."

Osteoarthritis is caused by a group of influences that include conformation, age, use, conditioning, footing, and numerous physiological factors. As osteoarthritis begins to develop in specific joints, the owner may see the characteristic signs of pain, inflammation, swelling of joints, stiffness in motion, and alterations in the horse's ability to perform normally. Recent research on a cellular level revealed how these clinical signs of poor performance and an inability to run, jump, or spin were caused.

We now know that damage and trauma to joint surfaces, from any number of causes, result in the formation and release of matrix metalloproteinases (MMPs), cytokines, and interleukin-1. These are specific proteins found at the joint surface that are important mediators of articular cartilage degeneration. Articular cartilage is the smooth, glass-like cartilage found on the surface of joints and the underlying support structure. Interleukin-1 is thought to turn on or further activate MMPs and most cytokines. Higher concentrations of these proteins result in accelerated joint damage. But other naturally occurring proteins that compete with MMPs, cytokines, and especially interleukin-1 exist. These proteins make up the arsenal of the gene therapy approach to joint protection.

IRAP

IRAP (interleukin-1 receptor antagonist protein) is the best known of this relatively new group of anti-arthritis products. IRAP is a naturally occurring protein that works to protect joints by occupying receptor sites on the membrane of cartilage cells. These receptor sites are specific locations where only a select number of proteins can fit in and attach themselves to the membrane. Like keys in a lock, when certain proteins fit in and attach to the articular cartilage cell membrane, they are then capable of exerting a specific effect on the cell. In the case of MMPs, cytokines, and interleukin-1, that effect is to release other components that degrade and damage the cartilage structure.

Constant and persistent exposure to these damaging proteins leads to the downward spiral of pitting, cracking, and thinning of cartilage and to eventual production of osteoarthritis.

Recent research has shown that IRAP also fits into these receptors and prevents MMPs, cytokines, and interleukin-1 from occupying those sites. The more IRAP present in the horse, the more receptors that can be blocked and the less articular degeneration possible.

IRAP therapy utilizes a gene sequence for that special protein that has been incorporated into a harmless virus. The virus-IRAP gene sequence is injected into affected equine joints, and the virus soon takes over cells in the joint and uses the horse's own cellular machinery to produce more IRAP.

David Frisbee, D.V.M., Ph.D., associate professor of clinical sciences at Colorado State who works closely with McIlwraith, reported in the 2000 Symposium on Gene Therapy: "Following a single, intra-articular injection of adenoviral vector [the virus containing IRAP] capable of driving the protein expression of IRAP, we demonstrated a decrease in lameness and decreased synovitis [inflammation of the joint capsule surface] and decreased [osteoarthritis] using gene therapy." This and other similar studies began the gene-therapy-versus-equine-arthritis era and pushed its use into the clinical setting.

Clinical use

Wes Sutter, D.V.M., M.S., a board-certified surgeon at the Ocala Equine Hospital, uses IRAP therapy and finds that it is beneficial in certain situations.

"IRAP is not generally the first therapy used with most cases of early [osteoarthritis]  since 70% to 80% of those cases will respond to sodium hyaluronate and corticosteroids," Sutter said.

Cases that return in three months with pain and inflammation, unresponsive cases, and horses with severe joints that have a history of poor performance even with corticosteroid use seem to be good candidates for IRAP therapy and have shown remarkable results. Logic dictates that early, mild cases of osteoarthritis should do better with this type of therapy, but it seems from research projects done in Colorado, Germany, and Oklahoma that even damaged joints with a history of little improvement with standard treatment respond to IRAP therapy and show some success. As long as there is functional cartilage lining the joint, gene therapy can show some improvement.

 "If IRAP was utilized in early mild cases of [osteoarthritis], I am sure that there would be improvement, as well, but the therapy may not be cost-effective in these situations," Sutter said.

Cases of bone cysts or holes below the joint surface seem to respond well to IRAP, as do horses affected with inflammation of the sesamoid bones (sesamoiditis) and inflammation of the covering of the cannon bone (periostitis or bucked shins).

To produce the IRAP product, 12 to 20 cubic centimeters (ccs) of the horse's serum are used. Treatment consists of a series of up to eight weekly intra-articular injections.

Cost of the treatment will vary between clinics. For horses previously affected with sometimes crippling arthritis that can now return to athletic function, IRAP is definitely worth the expense.

"With continued and expanded use," says Dr. Sutter, "veterinary clinicians will become better at identifying potential candidates for IRAP therapy, and the results will no doubt improve, as well."

Future of gene therapy

Gene therapy represents the newest innovation in the treatment and prevention of joint disease. But although it is a modern technology, gene therapy actually allows the body to do what it has best done all along. In 2002, James Richardson, M.D., a board-certified surgeon and professor of orthopedics at Keele University in England, wrote in the International Cartilage Research Society Newsletter:

"There is a great cleverness in each cell and learning to work with them, and to trust them to do the right thing in the right place is not new to surgery. We have always depended on the natural biology of tissue healing."

IRAP is the most recent approach to helping the body heal itself, and even newer types of gene therapies and products on the research horizon will continue this trend.

Kenneth L. Marcella, D.V.M., is a practicing veterinarian in Canton, Georgia.