Caspase proteins play a critical role in programmed cell death, and they can spur the immune system to fight off disease. But humans don't have a single caspase that can fulfill the functions needed to activate the immune system. Now, thanks to insights from dogs and cats, researchers have found they can modify a human caspase so that it operates as a single-protein signaling pathway.
The findings, reported Friday in the journal Science Immunology, offer key insights into complex innate immune pathways in people, the researchers said.
Scientists at Harvard Medical School and Boston Children's Hospital studied caspase protein families in dogs and cats to see how they compare with caspases in humans. Based on what they found in dogs, the researchers were able to unlock the mechanism by which human caspases cleave IL-1 proteins, which regulate immune and inflammatory responses. They then modified the human caspases so innate immune pathways could be "condensed" into one protein, they wrote.
That protein switches on NLRP3, a network of innate immune system receptors and sensors that elicit an inflammatory reaction.
"Our discovery of the mechanism of how IL-1 is cleaved by caspases provides an opportunity to create next-generation inhibitors of inflammation," said Jonathan Kagan, Ph.D., Harvard professor of pediatrics, in an email to Fierce Biotech Research.
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The NLRP3 protein complex is a hot target in biopharma. Ventus Therapeutics picked up a $100 million series B in April to support an NLRP3 inhibitor that penetrates the brain. Roche paid $451 million last September to buy Inflazome for its brain-penetrant NLRP3 inhibitors. NodThera and ZyVersa are lining up, too.
In order for NLRP3 to be activated, caspases have to perform two important actions, the Harvard-led team explained in the study. The researchers found that dogs exhibit a hybrid protein that can perform both activities and that cats have a similar hybrid caspase with a slightly different mechanism of action. With these insights in hand, the scientists then engineered the simplified version of the human caspase.
The development could inform new efforts at engineering combinations of immune pathways, which could, in turn, boost efforts to develop new immunotherapies, Kagan said. "Unlike prior approaches that affect all caspase functions, this new knowledge allows us to target specific aspects of inflammasome dependent inflammation."