Blocking enzyme shows promise as EBA treatment strategy
Compound targeting enzyme reduced skin damage in lab model
Treatment with SNT-6935, an experimental compound that acts to reduce the activity of an enzyme that breaks down proteins, reduced skin damage in a lab model of epidermolysis bullosa acquisita (EBA), a study showed.
The study, “Granzyme B inhibition reduces autoantibody-induced dermal–epidermal separation in an ex vivo model of epidermolysis bullosa acquisita,” was published in Experimental Dermatology.
Epidermolysis bullosa encompasses a group of disorders characterized by extremely fragile skin that is prone to severe blistering. Most types of EB are caused by genetic mutations that lead to problems making a particular type of collagen, a key structural protein that helps hold the skin and other bodily tissues together. EBA, however, is an autoimmune disorder in which the immune system makes antibodies that attack a form of this protein called type VII collagen.
Some studies have suggested that certain proteases — enzymes that can chop up proteins — may play a role in autoimmune disorders that affect the skin. Scientists in Germany and Australia conducted a series of experiments to investigate the role of a particular protease called granzyme B, which can be secreted by immune cells.
They used an established laboratory model in which samples of human skin are incubated in combination with immune cells and antibodies against type VII collagen, mimicking the autoimmune attack that drives EBA.
Additional factors likely at play
The scientists found that treatment with SNT-6935, a compound that blocks the activity of granzyme B, reduced the amount of tissue damage in this lab model of EBA. Specifically, SNT-6935 treatment resulted in less dermal-epidermal separation, meaning that the layers of skin were better able to stick together and less prone to forming blisters.
“Our data demonstrated that SNT-6935 dose-dependently abrogated EBA [antibody]-induced skin cleavage,” the researchers wrote, adding that the result “supports the potential of [granzyme B] inhibition as a therapeutic approach” in EBA and related diseases.
In theory, these data imply that the granzyme B enzyme itself probably plays a major role in driving tissue damage in EBA. However, the researchers found that just treating skin samples with granzyme B did not lead to the type of tissue damage that characterizes EBA, which suggests that additional factors beyond just this enzyme are necessary to drive the disease. Collectively, the data suggest that tissue damage in EBA is “the result of a complex interplay between proteases and other molecules,” the researchers concluded.
The researchers postulated that combining protease-blocking compounds like SNT-6935 with other drugs, such as immune-suppressing medications, might be a viable strategy for developing EBA treatments.
About the Author
