Researchers at Hospital for Special Surgery in New York City have identified a protein, known as IRHOM2, as the potential new target for drugs to treat patients with rheumatoid arthritis (RA).
The finding could provide an effective and potentially less toxic alternative therapy to tumor necrosis factor-alpha blockers (TNF-blockers), the mainstay of treatment for rheumatoid arthritis, and could help patients who do not respond to this treatment. Efforts to develop drugs that hone in on this new target are underway.
“This study is an elegant example of the capacity of basic science cell biologists to work with translational rheumatologists to address a clinically relevant question at a basic level. We have identified a clinically relevant target that can be applied to patients in the near term,” said Jane Salmon, M.D., Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at Hospital for Special Surgery (HSS), and an author of the study.
Rheumatoid arthritis, an autoimmune disease, is triggered, in large part, by TNF-alpha, a small signalling protein usually involved in launching protective systemic inflammatory responses. With excessive TNF production, however, immune cells can become activated inappropriately and cause tissue inflammation. This produces a number of diseases, including RA. While TNF-blockers help many RA patients, these treatments are very expensive, and some patients do not respond. For this reason, researchers have been searching for alternative targets in patients with inflammatory diseases against which drugs can be directed.
“TNF can be thought of as a balloon tethered to the surface of cells. To work, it must be cut loose by signaling scissors called TACE (TNF-alpha converting enzyme),” said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS. While blocking TACE could be another way to treat rheumatoid arthritis, researchers know this strategy would likely have side effects since patients lacking TACE are prone to skin infections and intestinal lesions.
Earlier this year, HSS investigators demonstrated that the TACE scissors are regulated by molecules called IRHOM1 and IRHOM2, which are thought to wrap around TACE and help it mature into functional scissors. They also demonstrated that mice that are genetically engineered to lack IRHOM2 lack functional TACE on the surface of their immune cells and don’t release TNF. Surprisingly, these mice are healthy, and do not develop skin or intestinal defects.
In the current study, HSS researchers set out to investigate why this paradox exists. After examining tissues of IRHOM2-deficient mice, they found that IRHOM2 regulates TACE on immune cells, whereas IRHOM1 is responsible for helping TACE mature elsewhere in the body, such as in brain, heart, kidney, liver, lung and spleen cells. The researchers then set out to determine whether blocking IRHOM2 could be a strategy to treat RA. They used a mouse model that mimics human rheumatoid arthritis in mice genetically engineered to be deficient in IRHOM2. They found that these rodents did not develop inflammatory arthritis and were otherwise healthy.
“When we tested mice that don’t have IRHOM2 in a model for inflammatory arthritis, we found they were protected and they were protected as well as mice that didn’t have any TNF,” said Dr. Blobel. Using drugs that inactivate IRHOM2 in humans, clinicians will be able to block the function of TACE only in immune cells. “We can prevent the deleterious contribution of TACE to rheumatoid arthritis patients and preserve its protective function in skin and intestines. With IRHOM2, we have a unique and unprecedented opportunity to inactive TACE only in certain cell types, and not in others, and there is currently no other effective way of doing that,” said Dr. Blobel. The researchers say the next step is to identify antibodies or pharmacological compounds that can be used to block the function of IRHOM2 and are safe in patients. The study will appear online in the Journal of Clinical Investigation and in the February 2013 print issue.