An angiogram 3D reconstruction showing the patient’s a giant vertebral fusiform aneurysm (arrow).

The study shows how genomic analysis can identify drugs that precisely target specific disease-causing mutations.

By Michael McCarthy

A collaboration of researchers from the University of Washington and Seattle Children’s Hospital has identified a mutation in a rare form of brain aneurysm, suggesting such aneurysms might be treated with a drug that has already been approved for the treatment of cancer.

An angiogram 3D reconstruction showing the patient’s a giant vertebral fusiform aneurysm (arrow).The finding suggests that more common forms of aneurysms may be caused by other yet undiscovered mutations that could also be treated with medication instead of high-risk surgical interventions.

“Right now, we are largely limited to surgical procedures such as craniotomy to clip or repair aneurysms or on endovascular treatments to place stents and coils,” said Manuel Ferreira, M.D., Ph.D., UW Medicine’s chief of neurological surgery, who led the research project. “Our

Credit: Michael McCarthy

Photo: Manuel Ferreira, M.D., Ph.D., UW Medicine’s chief of neurological surgery.

findings suggest that medications, in this case the well tolerated cancer drug sunitinib, may be able to treat some of these aneurysms,” he said.

 

Aneurysms occur when the blood vessel wall weakens. These weakened vessel walls bulge out and often burst, in some cases causing catastrophic bleeding, particularly when they are located in the brain.

Some aneurysms are caused by inherited genetic disorders, said Ferreira, but these disorders are relatively rare. In most cases, the cause of an aneurysm is unknown. Such aneurysms, known as sporadic aneurysms, have been thought to be the result of damage to the vessel wall caused by such factors as smoking and high blood pressure. “Our study is the first to identify a genetic cause for a sporadic aneurysm,” Ferreira said. “I suspect we’ll find other types of aneurysms have a genetic cause as well,” he said.

In the study, researchers began with the case of a young man who started to develop aneurysms at a very early age. Genetic evaluations done at major medical centers around the country had failed to find mutations typical of the inherited disorders associated with aneurysm.

The type of aneurysm he developed are called fusiform—or spindle-shaped—because they tend to be wide in the middle and taper at the ends. These are unlike the much more common form of aneurysms, saccular aneurysms, which form spherical, balloon-like bulges on the side of the blood vessel.

Curiously, the man’s aneurysms appeared only on the right side of his brain. He also had patches of skin that was discolored and abnormally stretchy that tended to be on the right side of his body, and his right arm and fingers were also abnormally long. The left side of his body, on the other hand, was almost entirely unaffected.

Ferreira wondered whether the patient’s aneurysms were caused by a condition called mosaicism. In this condition, instead of inheriting a mutation from a parent, in which case every cell in the body will carry the mutation, the mutation occurs during embryonic development. When this happens, tissues derived from the embryonic cell that acquired mutation tend to exhibit the disorder and those tissues that did not tend to be normal.

Ferreira wondered whether mosaicism could explain why his patient had the aneurysms and the skin and limb abnormalities on one side. To test this hypothesis, Ferreira working Dr. Peter Byer, M.D. and Michael Dorschner, Ph.D., genetics experts in the University of

Washington School of Medicine’s department of pathology and members of the Brotman Baty Institute, William Dobyns, MD of the department of pediatrics, and other colleagues set about to compare the genes from cells in the vessel walls affected by the aneurysm and cells from the affected skin with those from tissues that were not affected. They found the genes were the same except a change in one base pair in the DNA sequence of one gene.

That gene, Dorschner said, coded for a protein called platelet-derived growth factor receptor beta for PDGFRB. The mutation caused the change of one amino acid in a crucial part of the protein.

“We know platelet-derived growth factor receptor beta is involved in vascular development, so it made sense that if a mutation occurred sometime during embryonic development it could lead to the formation of defective vessel walls,” Dorschner said.

Normally, PDGFRB acts as a kind of “on-off” switch that regulates key cellular activities.. The change caused by the mutation, however, left PDGFRB stuck in the “on” position, sabotaging the receptor’s regulating function. Such activating mutations are called “gain of function” mutations.

Gain in function mutations in PDFGRB also play a role in a number of cancers and these have been successfully treated with a PDGFRB inhibitor called sunitinib. To see whether this drug might be used to treat fusiform aneurysms, the researchers created cell lines in which they inserted the abnormal gene from the first case and genes from five other cases that also had mutations affecting the same region of the protein.

They found the drug did indeed turn off PDGFRB in four of five of the cases, suggesting the drug might be able to prevent aneurysms from forming and shrink or stabilize those that

already exist. In the one case where it did not work, sunitinib was unable to bind to the mutated version PDGFRB and shut it down.

The findings suggest that mosaicism may be behind saccular aneurysms as well as other sporadic disorders whose causes are unknown, said Dorshner. “Mosaicism may play a greater role in disease than we’ve thought,” he said.

Funding: This research was supported by the National Cancer Institute (NCI) of the National Institutes of Health (P30CA015704), the National Institute of Neurological Disorders and Stroke (R01HL130996); the National Center for Advancing Translational Sciences (UL1 TR000423); University of Washington School of Medicine; the Fred Hutchinson Cancer Research Center; the Goertzen Foundation; and the Kapogiannatos Family fund.

Reference: Karasozen et al., Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms, The American Journal of Human Genetics (2019), https://doi.org/10.1016/j.ajhg.2019.03.014