About five of every 100 people have a ballooning, weakened artery in their brain called an aneurysm, though the vast majority will never know it. Still, in the rare case that an aneurysm pops, or ruptures, it can be lethal. As many as 40% of people with a ruptured brain aneurysm will die, and 40% of survivors will be left with brain damage.
Brain aneurysms at risk of rupture can only be treated with surgery, and that may not be possible if the aneurysm is in a hard-to-access location. But a new study hints at another solution: the cancer drug sunitinib. Commercialized by Pfizer as Sutent, the drug appears to prevent aneurysms in mice, according to findings published June 14 in Science Translational Medicine by researchers from Japan’s RIKEN Center for Brain Science.
“It was a groundbreaking finding, opening the possibility to develop medications for aneurysms, which currently should be treated only by surgical methods,” study leader Hirofumi Nakatomi, M.D., Ph.D., told Fierce Biotech Research in an email.
There are two main types of aneurysms. About 90% are intracranial saccular aneurysms, or ISAs, which form berry-like bulges along the outside of an artery. Another 3-5% are intracranial fusiform aneurysms, or IFAs, which expand the blood vessel into a spherical shape. ISAs are more likely to rupture but are also easier to treat. IFAs rarely rupture, but if they do, the patient has a worse prognosis.
Most brain aneurysms of any form are sporadic; around 10% run in families. The researchers wondered whether there might be other risk genes and mutations involved in aneurysm development, though they expected that their contribution would be small. To find out, they started by performing a broad type of genetic sequencing called whole-exome sequencing, or WES, followed by a more granular type called targeted deep sequencing, or TDS, on artery samples taken from patients. The samples included 65 arteries with aneurysms and 24 without.
The scientists were surprised by the findings: 92% of the aneurysms had mutations in at least one of a set of 16 genes, none of which were found in the normal samples. Six of the mutations showed up in both IFAs and ISAs, while another 10 mutations appeared only in one or the other. All of the mutations common to both types of aneurysm activated the NF-kappa beta signaling pathway, which has previously been shown to be involved in aneurysm formation.
“These results suggest that the mutations identified in these 16 genes are relatively unique to sporadic intracranial aneurysms,” the researchers wrote in the paper. They also suggest that most aneurysms might be triggered by the mutations, Nakatomi noted in a press release.
One of the most common mutations was in the gene PDGFRB, which gives rise to the platelet-derived growth factor receptor beta protein (also known as PDGFRB). The PDGFRB protein is a receptor tyrosine kinase involved in cell signaling and cardiovascular system formation; mutations in its encoding gene have previously been linked with rare tissue overgrowth syndromes, but not with brain aneurysms.
The fact that both saccular and fusiform aneurysms had PDGFRB mutations “indicates the gene mediates a pivotal role in intracranial aneurysm formation” in both subtypes, Nakatomi said.
Next, the researchers used a technique called spatial transcriptomics to see if PDGFRB mutations were present throughout an aneurysm's tissue layers, which would help explain the mechanics behind its formation. The results showed that the mutations were limited to the outer layer of cells in small aneurysms but extended into the inner layers of larger ones. This suggests that a gene mutation on the artery surface initially triggers the aneurysm to form; the mutated cells then proliferate and spread into the inner layer of the artery, weakening the vessel wall, Nakatomi explained.
The scientists then turned to cells grown in a petri dish to hone in further on the impact of PDGFRB mutations. They found that cells with the mutations migrated more quickly than wild-type cells and showed signs of inflammation. Treating the cells with sunitinib, a tyrosine kinase inhibitor, slowed their migration speed and reduced inflammation. This both confirmed the role of PDGFRB mutations and showed that it was possible to stave off their effects with a drug.
Finally, the team tested their findings in mice. They started by using an adeno-associated virus vector to deliver a mutated PDGFRB gene to cells in the basilar artery of the animals’ brains, a site that only accounts for 3-5% of aneurysms but is one of the hardest to treat. A month later, the artery had weakened and ballooned into an IFA twice its initial size, again confirming the mutation could cause aneurysms.
But the researchers didn’t see the same effect in mice who had also been given a dose of sunitinib daily beginning on the first day after viral infection. The size of their basilar arteries was roughly the same as controls, indicating that the drug was able to prevent aneurysms from forming.
“Our finding that some of these high-risk … cases have a common genetic cause, namely, mutations in PDGFRB, opens a new avenue of research towards future development of pharmacological interventions for [aneurysm], either alone or in combination with existing surgical options,” the researchers wrote in their paper.
While the findings around sunitinib were encouraging, the team didn’t test whether it could stabilize or reduce the size of already-formed aneurysms. That will need to be investigated in future studies, they noted in the paper.
And even if the drug could do that, there’s another problem: while PDGFRB mutations were common, they weren’t present in every case. Having no way to biopsy brain arteries makes it challenging to identify which ones to target right now, Nakatomi noted, though new technology could eventually make it possible.
Still, there may be a place for the drugs sooner rather than later—as a preventive strategy for aneurysm recurrence, which happens in around 10% of patients who undergo surgery.
“We anticipate that those drugs can be applicable relatively soon as preventive medications of recurrence of aneurysms after surgical treatments,” Nakatomi added.