New Treatment Target For Traumatic Brain Injury Revealed By Study

The roughly 1.5 million Americans who survive a severe brain injury each year have wildly different health outcomes. These injuries raise the possibility of developing dementia in the future in addition to causing impulsivity, depression, loss of coordination, and concentration issues.

Scientists at Gladstone Institutes have been studying the molecular mechanisms underlying neurodegeneration caused by traumatic brain injuries and, more importantly, how to target this process to prevent long-term injury, in response to the glaring absence of therapies for this prevalent condition.

“We set out to address the fundamental question of exactly what happens in the brain after injury to ignite the damaging process that destroys neurons,” explains Gladstone Institutes scientist Jae Kyu Ryu, PhD, who leads the scientific program at Katerina Akassoglou’s lab.

According to the Centers for Disease Control, the majority of traumatic brain injuries result from falls, automobile crashes, or violent attacks; however, many also arise from sports-related incidents or specific military actions, such explosions. Each time, there is an external force great enough to shift the brain inside the skull, seriously rupturing the blood-brain barrier and letting blood in.

According to Ryu, the study’s lead author and author of the Journal of Neuroinflammation article, “We knew that a specific blood protein, fibrin, was present in the brain after traumatic brain injury, but we didn’t know until now that it plays a causative role in brain damage after injury.”

For an extended period, Ryu and others in Akassoglou’s laboratory have studied the mechanism by which blood leaks into the brain cause neurologic illnesses. This involves subverting the brain’s defense mechanisms and initiating a series of detrimental, frequently permanent consequences. The offending protein is fibrin, which typically aids in blood coagulation.

“Toxic immune responses in the brain are triggered by blood leaks and drive neurodegeneration across many neurological diseases,” explains Gladstone senior investigator Akassoglou, who also serves as the director of the Center for Neurovascular Brain Immunology at Gladstone and UCSF.

“Neutralizing the toxic immune responses in the brain paves the way to new therapies for neurological diseases.”

Neurodegeneration is caused by fibrin seeping into the areas important for cognitive and motor functioning in disorders like multiple sclerosis and Alzheimer’s. This is due to aberrant leaks in the protective blood-brain barrier.

In this instance, however, blood seeps into the brain as a result of the traumatic brain injury itself. For the first time, the new study demonstrated that fibrin is the cause of harmful inflammation, the degeneration of healthy immune cells, and the release of neurodegenerative toxins.

The Gladstone group examined the brains of mice and individuals who had suffered traumatic brain injuries using cutting edge imaging techniques. Additionally, they created three-dimensional images of an entire mouse brain that was intact, demonstrating traumatic brain injury-related fibrin accumulation and blood-brain barrier breaches.

Fibrin was found in the brains of mice and humans along with activated immune cells.

“It became clear that fibrin is activating these immune cells,” Ryu says. “We realized that we can prevent the toxic effects if we could block fibrin, but we had to do it in a precise way.”

Utilizing genetic methods, the team was able to prevent fibrin from stimulating immune cells while maintaining the protein’s advantageous blood-clotting properties. This is particularly important in cases of severe brain injuries since individuals who were on anticoagulant drugs prior to their injury have been reported to experience significant bleeding into the brain.

A therapeutic monoclonal antibody that only targets the inflammatory characteristics of fibrin and has no negative effects on blood coagulation was previously created by Akassoglou’s team.

In mice, this fibrin-targeting immunotherapy offers protection against Alzheimer’s and multiple sclerosis. Phase 1 safety clinical trials for Therini Bio’s humanized variant of this first-in-class fibrin immunotherapy are currently underway.

“It’s exciting to have a therapeutic option to neutralize blood toxicity in neurologic diseases,” Ryu says. “Future studies are needed to test the effects of the fibrin immunotherapy in traumatic brain injury.”

“This study identifies a potential new strategy to diminish the devastating impacts of brain injuries,” says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.

“Brain injuries can have a tremendous impact on a person’s physical skills, emotional stability, and cognitive capacities, affecting all aspect of their life. It will be fascinating to investigate whether preventing fibrin from having its disease-promoting effects can enhance brain surgery results and lessen disability when applied following traumatic brain injuries.