IAs – ID’d

It is known as “the silent killer” for a reason; an intracranial aneurysm (IA) can strike lethally and without warning. But without useful biomarkers, meaningful intervention is more than challenging. A recent paper in the Journal of Translational Medicine hints at a new approach, by highlighting a signature for IAs hidden within the RNA transcriptome of circulating neutrophils (1).

“When we studied the pathology of aneurysm, we realized that it was an inflammatory response – as is the rupture,” explains Hui Meng (centre), Professor of Mechanical, Aerospace and Biomedical Engineering and Neurosurgery at the University of Buffalo, and one of the project leaders. Trained in fluid dynamics, Meng was initially interested in the hemodynamic mechanisms of aneurysm formation. She quickly became aware of a lack of screening tools and frequently witnessed patients arriving at the hospital medical center with ruptured aneurysms. “We hypothesized that there might be a signature in the blood that could tell us when aneurysms were forming,” she says. To develop the idea, the team looked for external support. “We found collaborators, such as James Jarvis (left), who was developing RNA sequencing biomarkers for another inflammatory disease: juvenile arthritis.” Meng explains. “And that’s how we started to design a pilot study; we ran a small study of just six patients – and too our surprise there was a significant difference.”

Next to enter the story was the Brain Aneurysm Foundation. “It’s the only foundation we know of that’s devoted to this silent killer,” says Meng. The grant the group received was donated by Jeff Harvey, whose wife, Carol, suffered a fatal IA. “Even after the very preliminary data, Jeff asked us when we would have a blood test,” Meng recalls. “He was the one driving us – and it made us realize that we really could have an enormous impact.”

The group’s work was not met with such a warm welcome by the wider scientific community; the group’s first paper (2), finally published in PLOS One in January 2018, encountered significant skepticism. “We tried a few journals and they really didn’t want to take a chance,” says Meng. Vincent Tutino (right), Research Assistant Professor in the Department of Neuroscience at the University of Buffalo, whose PhD studies sparked the initial research, explains, “RNA profiling in the blood is very new. So whilst this paradigm is common in inflammatory diseases, such as arthritis and lupus – or in cancer, it really hadn’t been seen much in vascular disease – and nothing specifically to aneurysm.”

To test their hypothesis, the team extracted neutrophil RNA from blood samples of 40 patients – 20 of whom had unruptured IAs confirmed through angiography. Using a machine learning approach, the team was able to identify IA patients with an accuracy of around 80 percent (based on 26 differently expressed transcripts).

Undeterred by initial skepticism and spurred on by early success, the researchers have already established a startup company to market the test – Neurovascular Diagnostics. Tutino, who is also President and CEO of the new company says, “To bring a diagnostic platform to market, we need to find these biomarkers in a patient’s whole blood.” The company will also need to verify that their markers are specific to aneurysm. “Ideally, we will have larger cohorts, with multiple control groups, including patients who have other vascular pathologies,” says Tutino.

“It’s a snowball effect,” says Meng. “As we gain more acceptance for our work, we should gain more funds to do it.”

Meng also believes that the work could have broader application. “Generally, I think the methodology can be transferred,” she explains. “Will we see similar types of blood test for other vascular disease? I’m pretty optimistic about that!"