'Mutant' origin of brain aneurysms found, leading to first drug cure
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New research has revealed a series of interconnected mutations responsible for causing intracranial aneurysms— dangerously weakened blood vessels in the brain that pose an imminent risk of rupture.
These mutations have been found to target a single biological signaling pathway, which has paved the way for developing the first-ever pharmaceutical treatment that successfully inhibits this pathway in mice.
The study, published in Science Translational Medicine on June 14, offers new hope for eventually combatting this life-threatening condition in humans.
What are the two types of aneurysms?
Intracranial aneurysms, weakened blood vessels in the brain, often go unnoticed until they rupture, leading to life-threatening bleeding. Two types of these aneurysms exist intracranial fusiform aneurysms (IFAs) and intracranial saccular aneurysms (ISAs), with ISAs comprising about 90 percent of cases.
The existing treatment options involve surgery, which carries risks, especially for aneurysms in sensitive locations. Therefore, finding non-surgical alternatives is crucial.
To address this challenge, researchers at the RIKEN Center for Brain Science (CBS) in Japan embarked on a study to understand the origins of intracranial aneurysms and explore potential treatments.
The RIKEN team conducted comprehensive genetic sequencing of aneurysmal and normal arteries, analyzing the entire exomes of these cells.
They discovered that six genes were present in both IFAs and ISAs but not in non-aneurysmal arteries. In comparison, 10 other genes appeared exclusively in either IFAs or ISAs.
"The unexpected finding that greater than 90 percent of aneurysms had mutations in a common set of 16 genes indicates that somatic mutation could be the major trigger in most cases," said project leader Hirofumi Nakatomi in a press release.
Further investigation revealed that all six common genes triggered the same 'NF-κB' biological signaling pathway. To explore potential treatments, the researchers focused on one of these genes, PDGDRB, and demonstrated its involvement in aneurysm development.
Enter 'sunitinib,' the new inflammation-blocking drug
Using sunitinib, a drug that blocks abnormal signaling associated with PDGDRB mutations, successfully inhibited cell migration and inflammation in cultured cells.
Taking their research further, the team created a mouse model of intracranial aneurysms by introducing mutant PDGFRB into the basilar artery.
The mice treated with sunitinib showed normal-sized and robust arteries, whereas those without treatment experienced significant artery expansion and weakening. This groundbreaking result demonstrated that pharmacological intervention could effectively prevent aneurysm progression.
While additional research is needed to determine the efficacy of this drug treatment in humans, Nakatomi outlined that perhaps the more significant challenge lies in detecting unruptured intracranial aneurysms.
"Unruptured intracranial aneurysms are usually detected by Magnetic Resonance Angiography or Computed Tomography Angiography during health checkups. If these tests are not available, then aneurysms are undetectable until they burst," explained Nakatomi.
He argued that in Japan, where this research was conducted, many people could receive these tests as part of their annual health checkup, making the development of drug treatments more valuable.
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