The family of serine proteases known as granzymes – granule secreted enzymes – is a well-known target in the cancer space. Stored in cytotoxic T cells and natural killer cells, granzymes are released – with the help of pore-forming protein perforin – into the infected cell to trigger apoptosis.

It was believed that granzymes were found only in those two types of immune cells. But recent discoveries have shown them to be much more ubiquitous.

"In the last few years, people began asking, 'Does all the granzyme go inside the cell?'" said Alistair Duncan, president, CEO and co-founder of 2008 start-up Vida Therapeutics Inc.

The answer was no. In clinical studies looking at a number of chronic inflammatory diseases, researchers found extracellular granzymes – particularly granzyme B – present in body fluid. And in cases of inflammatory disease, those granzyme B levels were higher.

But where is the granzyme B coming from? "It turns out there are other cells beside immune cells," such as mast cells, macrophages, chondrocytes and keratinocytes, that also release granzyme B, and those cells do so without the assistance of perforin, Duncan told BioWorld Today. Basically, "this protease is running amok without any endogenous inhibitor, nothing to block its activity."

In rheumatoid arthritis, for example, chondrocytes release granzyme B, which degrades aggrecan, a key substrate in the extracellular matrix. That assault creates an inflammatory response, triggering the release of more immune cells, which continue doing damage. "It's a cycle," he explained.

A spinout of the University of British Columbia, Vida's technology was developed by co-founder David Granville, the company's chief scientific officer. Granville, a cardiopathologist by training, started by looking at atherosclerotic plaque. "He was really trying to understand the role on these pathologies," Duncan said. And those discoveries, at the time, "were really going against the dogma associated with granzymes."

There are five members of the granzyme family. Vida – whose name means "life" – is taking aim at granzyme B first, which targets a number of substrates that make up the extracellular matrix such as aggrecan and decorin, both proteoglycans.

Decorin's purpose "seems to be to organize and decorate, if you will, collagen," Duncan said, comparing the collagen weave to a cable-knit sweater. With aging, the weave loses its tensile strength, and pressure causes ruptures (in aortas, for example) or tearing (as in skin).

Using a model of aortic aneurysms – specifically an apolipoprotein E (ApoE) knockout mouse with a high-fat diet – angiotensin II was introduced, resulting in spontaneous aneurysms in the mouse aortas. But when mice were also knocked out with granzyme B, they were able to attenuate the aneurysm. The same result occurred when a granzyme B blocker was introduced to the ApoE knockout model, "and we did it a third time with an antibody inhibitor of granzyme B," Duncan said.

But going into cardiovascular drug development was a daunting prospect. "It's a very hard place for a start-up company to move into without some significant support," he acknowledged.

The role of granzyme B, however, offered additional pathways. For one, researchers looking at the ApoE knockout mouse studies noticed an interesting side effect when granzyme B was blocked: "The skin of these mice looked fabulous, for lack of a better word," Duncan said.

While Vida's technology does cover the anti-aging aspect, Duncan said the company identified dermatology as its lead program. "We think it's the fastest way to the clinic."

Vida has been working for the past year and a half on a topical granzyme B inhibitor in large animal models. "We still haven't determined exactly what to do," though the firm is considering possibly chronic wounds or keloid scarring.

To date, Vida has raised about C$6 million (US$5.8 million), including a C$1 .8 million equity financing round last month with lead banker BDC Venture Capital.

Over the past 12 to 18 months, the company has built "a lot of exciting momentum and science behind us," Duncan said. "With additional funding in place . . . we aim for the clinic in the next 12 to 14 months."