New research from the University of Alberta’s Faculty of Medicine & Dentistry is trailblazing a potential new pathway for the treatment of multiple sclerosis (lat. Sclerosis multiplex, MS). The research examines a novel therapeutic strategy to reduce inflammation in the brain - a key contributing factor to the muscle disability associated with multiple sclerosis. According to the researchers, most current MS treatments act on the immune system to reduce inflammation on the brain. The downside is that as medications get stronger, they suppress the immune system to the point that patients must cope with significant side-effects. In the study, the University of Alberta scientists examined an enzyme called granzyme B in cytotoxic cells as a possible therapeutic target for reducing inflammation without significantly suppressing the immune system response.
Cytotoxic cells are typically used by the body to kill virus-infected cells. In the case of MS, though, they are redirected against the host. The enzyme, granzyme B, acts as a weapon, damaging nerve cells and other components in the brain. In the study, researchers found that by suppressing granzyme B through a recently discovered inhibitor called serpina3n, they could significantly reduce the progression of MS symptoms in both human cells and pre-clinical models. According to Fabrizio Giuliani, senior author of the study and associate professor in the neurology division of the Faculty of Medicine & Dentistry, they can interfere with some of the weapons these cytotoxic cells use to induce damage to the nerve cells in the brain, but without disrupting the other positive functions that these cells have. This molecule, serpina3n, will block the damage caused by granzyme B that induces the neurodegeneration in this disease, and the neurodegeneration strongly correlates with the disability.
By targeting granzyme B, the body’s inflammatory response is minimally affected. He adds that by interfering with the early stages of inflammation to the brain in MS patients, progression of the disease can be slowed. Granzyme B was discovered previously at the University of Alberta by study co-author Chris Bleackley, a professor in the Department of Biochemistry. He also contributed to the discovery of serpina3n along with Raymond Rajotte, a professor in the Department of Surgery. Scientists believe that the results of this study are very exciting and quite unexpected. They are a great example of how basic research can have surprising and beneficial applications in the treatment of human diseases. Scientists are already looking to next steps in their research. They are currently preparing experiments using human analogs of serpina3n that will further examine the impact of inhibiting granzyme B in patients with multiple sclerosis.
Researchers consider if they can induce neuroprotection, there is a good possibility they can decrease the rate of disability that is associated with inflammation in the brain. Study funding was provided by the MS Society of Canada and the Canadian Institutes of Health Research.