Protecting against influenza

By Betty Zou

A drug discovery from Sunnybrook Research Institute (SRI) is showing great promise in changing the way we fight flu. The drug, called vasculotide, significantly improved survival in mice infected with influenza virus, even when it was administered 72 hours after the infection.

Dr. Paul Van Slyke designed the drug when he was a PhD student working in the lab of Dr. Dan Dumont, a senior scientist in Biological Sciences at SRI. The drug works by attaching to a protein called Tie2, which functions as a receptor on the cell surface. Tie2 sits at the top of a signalling pathway that is critical for angiogenesis, the process by which new blood vessels are formed from existing ones. Growth factor proteins called angiopoietins modulate the activity of the Tie2 pathway—angiopoietin 1 (Ang1) turns it on whereas angiopoietin 2 (Ang2) shuts it off. “The idea is that in [some diseases], the bad guy Ang2 is the predominant player,” says Dumont. “What we want to do is tilt the balance back with an Ang1-like molecule.”

That’s where vasculotide comes in. In early laboratory studies, Van Slyke showed that the drug mimics the actions of Ang1 by binding to Tie2 and activating the signalling pathway. He also found that vasculotide can speed wound healing and help maintain the endothelial barrier, a tightly compressed layer of cells that form the inner lining of blood vessels to prevent their contents from leaking out.

These findings were critical to establishing their collaboration with Dr. Warren Lee, a scientist at the Keenan Research Centre for Biomedical Science at St. Michael’s Hospital. Lee studies the role of endothelial barrier function and vascular leakage in acute respiratory distress syndrome (ARDS), a potentially fatal complication of flu. Acute respiratory distress syndrome occurs when the endothelial barrier becomes more permeable and fluids leak out of the blood vessels to accumulate in the lungs. On their collaboration with Lee, Van Slyke says, “I thought [he] was probably the right person and it would provide a fusion of the right drug with the right ideas. Basically it took off from there.”

Vasculotide works as a molecular lasso, with each molecule of vasculotide binding and bringing together four Tie2 receptors. This activates the Tie2 signalling pathway to promote wound healing and reduce vascular leakage. Image courtesy of Dr. Paul Van Slyke.

Because vasculotide strengthens the endothelial barrier to prevent leakage, treatment with the novel drug resulted in less fluid accumulation in the lungs of infected mice and, consequently, greater survival.

“It’s well known that [in] influenza infection, an earlier approach will almost always provide a better benefit than a delayed administration of a therapeutic drug,” says Van Slyke. “What Warren determined was that, at least in the case of vasculotide, you could get equivalent protection even delivering [the drug] 72 hours out and there was a trend toward improvement at 96 hours.”

To be effective, current flu medications like Tamiflu, which targets the virus itself, need to be delivered within 24 hours of infection. This is a challenge clinically because many patients do not exhibit symptoms within the first 24 hours when the optimal time for treatment has already passed.

Moreover, since vasculotide acts directly on the host, it was equally protective against three different strains of influenza. “This approach is really strain agnostic,” says Van Slyke. “From the standpoint of broad protection across multiple strains, we think this is a major step forward.”

The findings were published in Scientific Reports on June 5, 2015 and picked up by media outlets in Canada and across the world.

Dumont and Van Slyke have spun out a company, Vasomune Therapeutics, to commercialize vasculotide and bring it to the clinic. They envision vasculotide being used in a critical care setting primarily to treat acute kidney or lung injury, and ARDS, all of which are characterized by a loss of endothelial barrier integrity and profound vascular leakage. To explore how vasculotide might be used to treat other diseases with vascular leakage, they have formed academic collaborations and are supplying the drug free of charge to their collaborators.

“[Collaborations] provide third-party, independent validation,” says Van Slyke, who is the chief scientific officer at Vasomune. “It’s important that other people work with [vasculotide] and see the same results we do.”

Dumont, who is also a professor at the University of Toronto, believes that these collaborations add value to their business model. Critical to the success of these partnerships is the sharing of information, particularly with regard to how to administer the drug. “What we’ve learned is the dosing—how much to give an animal, how often and when to give it,” he says. “That [information] we share with everyone.”

Both Dumont and Van Slyke credit much of their success to the research community at SRI and U of T, which enabled them to have discussions with a diverse group of people whose expertise and advice helped to guide vasculotide’s development. “We’ve had good fortune throughout,” says Van Slyke. As Louis Pasteur said, however, “Fortune favours the prepared mind.”