A research team from the University of Alberta, Canada, is exploring a new therapeutic way of reducing brain inflammation in multiple sclerosis (MS) patients with fewer side effects. The study, titled “Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo,” appeared in the Journal of Neuroinflammation.
Most available MS treatments are directed toward the immune system to lessen inflammation on the brain, a key contributor to the muscular disability exhibited in the disease. However, the constant suppression of the immune system under increasingly stronger treatments can induce severe side effects. In the study, researchers took a new approach. They examined an enzyme, known as granzyme B, in immune cytotoxic cells as a potential therapeutic target for reducing inflammation without significantly suppressing immune system response.
Cytotoxic cells normally help the body to eradicate virus-infected cells. But, in MS patients, granzyme B acts as a weapon, destroying nerve cells and other components of the brain.
The researchers found that if granzyme B was suppressed through a newly identified inhibitor, serpina3n, it was possible to significantly reduce MS symptoms’ progression. The study was conducted in human cells and in a preclinical mouse model.
“We 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,” Dr. Fabrizio Giuliani, senior study author and an associate professor in the neurology division of the university’s Faculty of Medicine & Dentistry, said in a press release. “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.”
As Dr. Giuliani explained, suppressing granzyme B has a minimal impact on the body’s inflammatory response. Furthermore, delivering this treatment soon after the first symptoms of inflammation appear in MS patients’ brains appeared to slow disease progression. “In our models, we haven’t seen that the disease disappears. The disease is still there, the inflammation is still there, but there’s not as much damage in the nerve cells that would induce a permanent disability,” noted Dr. Giuliani.
Granzyme B was discovered by the study’s co-author, Dr. Chris Bleackley, a professor in the Faculty of Medicine & Dentistry’s Department of Biochemistry. Dr. Bleackley also assisted in the discovery of the serpina3n inhibitor. “The results of this study are very exciting and quite unexpected,” said Dr. Bleackley. “They are a great example of how basic research can have surprising and beneficial applications in the treatment of human diseases.”
The research team is now planning experiments using human analogues of serpina3n to investigate the effects of inhibiting granzyme B in MS patients. “The importance of this is that you can see where it’s leading. You can see almost an immediate target,” Dr. Giuliani concluded. “This could eventually open the door to a new stream of treatments. If we can induce neuroprotection, there is a good possibility we can decrease the rate of disability that is associated with inflammation in the brain. If it works as we think, this will make an impact on the treatment of MS patients.”
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