Research Profile – Turning Back the Clock

Targeting an immune enzyme could help treat aging skin and blood vessel disease.

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An enzyme that helps destroy diseased cells is showing promise as a target to prevent skin from aging and improving the health of blood vessels.

The enzyme, known as Granzyme B (GrB), is found inside many immune cells. It is generally released as part of the arsenal of proteins that attack and dismantle damaged or infected cells. But it turns out that GrB also plays a role in the aging of skin, the health of blood vessels and in inflammation.

Researchers ignored GrB for decades, according to Dr. David Granville, associate professor of pathology and laboratory medicine at the University of British Columbia (UBC). It was thought that it played a redundant role in immune-mediated killing of cells and not much else.

"GrB targets diseased cells, enters them and triggers them to self-destruct. Beyond that, little was known about this enzyme or what else it might do," he says.

But UBC researchers took another look and discovered that GrB can actually leak out of immune cells as part of the aging process. And when it leaks out, it is not programmed to target specific, diseased cells. Instead, it accumulates outside of cells where it damages surrounding healthy tissue, leading to classic signs of aging – such as skin that is less elastic, and blood vessels with less integrity and strength.

Armed with a better understanding of GrB's activity, researchers are exploring whether the enzyme could be a target for therapies that treat blood vessel problems, as well as for certain skin diseases. Molecules that block GrB may even be useful as products that help keep skin looking more youthful.

Studies in animal models support this idea. With the help of funding from the Canadian Institutes of Health Research, Dr. Granville and his colleagues used mice lacking the gene that causes GrB to be produced to see how the absence of the enzyme affected blood vessel health.

"We found these mice had improved blood vessel integrity and that mice with atherosclerosis [hardening of the arteries] and aneurysm [weakness in the wall of a blood vessel that can cause it to burst] lived longer. Interestingly, we also found that not having GrB prevented some of the changes you see in aging skin," he says.

In fact, GrB attacks and breaks down specific proteins that are abundant in the skin and are responsible for regulating the tensile strength of collagen in the skin – features related to skin strength and elasticity. Levels of GrB actually increase with sun exposure and may be an important contributing factor to sun-damaged skin.

The research has generated so much excitement that the UBC industry liaison office helped Dr. Granville and his team establish a spin-off biotech company, viDA Therapeutics. "We're looking at a number of different diseases associated with aging and inflammation," says Dr. Granville.

The work could go beyond skin and blood vessels. In recent years, GrB has been found in cells in the joints and within skin cells themselves. In the joints, it might contribute to some of the damage seen in rheumatoid arthritis. According to Dr. Granville, treatments targeting the enzyme could also be used for chronic skin wounds and a variety of diseases associated with aging, degeneration and inflammation.