New treatment target for traumatic brain damage revealed by study

each year after suffering a catastrophic brain injury. 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 behind neurodegeneration caused by traumatic brain injuries and, more importantly, how to target this process to avoid long-term injury, in response to the glaring absence of therapies for this prevalent condition.

“Our goal is to investigate the basic question of precisely what happens in the brain following injury to start the destructive process that kills neurons,” explains Gladstone Institutes scientist Jae Kyu Ryu, PhD, who leads the research program at Katerina Akassoglou’s lab.

According to the Centers for Disease Control, the majority of traumatic brain injuries originate from falls, automobile collisions, or violent attacks; however, many also arise from sports-related incidents or specific military actions, such explosives. Each time, there is an external force great enough to shift the brain within 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, often 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 scientist Akassoglou, who also serves as the head of the Center for Neurovascular Brain Immunology at Gladstone and UCSF.

“Developing new treatments for neurological illnesses is made possible by neutralizing the harmful immune responses in the brain.”
Abnormal breaches in the blood-brain barrier enable fibrin to infiltrate into regions crucial for cognitive and motor processes, leading to neurodegeneration in disorders like multiple sclerosis and Alzheimer’s.

In this instance, however, blood seeps into the brain as a result of the traumatic brain injury itself. For the first time, the new research 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 together with activated immune cells.

According to Ryu, “it became evident that fibrin is stimulating these immune cells.” “We realized that if we could block fibrin, we could prevent the toxic effects, but we needed to do it precisely.”

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 accident have been reported to have 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 studies for Therini Bio’s humanized variant of this first-in-class fibrin immunotherapy are now underway.
“Having a treatment option to counteract blood toxicity in neurologic diseases is exciting,” Ryu remarks. “More research is required to evaluate the impact of fibrin immunotherapy in traumatic brain injury.”

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

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