Neutrophils play a crucial role by engulfing pathogens and releasing enzymes that kill invaders to fight infections. When they are activated by infection, neutrophils can release neutrophil extracellular traps (NETs), web-like structures consisting of DNA and proteins, which trap and kill pathogens as a part of the normal host defense mechanism. However, too much NET formation can significantly damage tissues, thus contributing to inflammation. Now, a newly developed compound that reduces harmful inflammation in rats caused by overactive neutrophils shows promise as a safer treatment for various inflammatory diseases in humans. The team of researchers from Hokkaido University and Alivexis investigated a recently-developed drug candidate, MOD06051, which reduces harmful inflammation in rat models by targeting neutrophils.
The results of their joint research were recently published in Nature Communications in an article titled, “Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders.”
“We found that MOD06051 works as a selective inhibitor for Cathepsin C (CatC), a key regulator that activates multiple enzymes inside of neutrophils known as neutrophil serine proteases (NSPs),” explained Yoh Terada, PhD, co-author and CSO of Alivexis. “One such NSP is neutrophil elastase, an enzyme involved in killing pathogens but also an essential factor for NET formation.”
The scientists found that inhibiting CatC reduces the active form of neutrophil elastase and decreases the ability of neutrophils to form NETs. Excessive NET formation has been linked to several diseases, including vasculitis, lupus, rheumatoid arthritis, and diabetes.
“When we tested the compound in rats that have a specific type of vasculitis, it decreased the disease severity, which was evident by reduced inflammation and damage in the blood vessels, especially in their kidneys and lungs,” said Akihiro Ishizu, a professor at Hokkaido University and leader of the study. “Our findings suggest that CatC inhibition shows promise as a new treatment strategy to reduce neutrophil overactivation and improve conditions in diseases where overactive neutrophils and excessive NET formation play a critical role. This approach differs from current treatments that may have broader immunosuppressive effects.”
Current treatments for inflammatory diseases often involve the use of glucocorticoids and immunosuppressive drugs which suppress the immune system’s activity as a whole and can lead to secondary immunodeficiency, increasing the risk of opportunistic infections. By specifically targeting the activation of multiple NSPs through CatC inhibition without broadly suppressing the immune system, MOD06051 potentially offers a safer alternative that could reduce the risk of infections and other side effects.
These findings pave the way for further research and clinical trials to evaluate the safety and efficacy of MOD06051 in humans. The team hopes that this novel approach holds the promise of providing safer and more effective therapies for patients around the world suffering from a variety of inflammatory diseases, improving their quality of life.
