Preventing Brain Damage in Preterm Babies

“As a neonatologist and neuroscientist, it’s frustrating that we don’t have any treatments to counteract the harmful effects of bleeding in the developing brain, even though we know it often leads to lasting problems,” says Petersen, director of the Neuro-Intensive Care Nursery at UC San Francisco (UCSF), associate professor of pediatrics at UCSF, and a visiting scientist at Gladstone Institutes. “Adding to this frustration, we’ve had very little understanding — until now — of why and how this bleeding is so closely tied to the long-term neurological issues these babies often face.”

In a study that appears in Proceedings of the National Academy of Sciences (PNAS), Petersen and an interdisciplinary team of physicians and scientists from Gladstone and UCSF shed light on this vexing medical condition, showing for the first time that a blood protein called fibrin blocks an essential biological process that drives brain development in early life.

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Discovery of How Blood Clots Harm Brain and Body in COVID-19 Points to New Therapy

In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also suppressing the body’s ability to clear the virus. Importantly, the team also identified a new antibody therapy to combat all of these deleterious effects.

Published in Nature, the study by Gladstone Institutes and collaborators overturns the prevailing theory that blood clotting is merely a consequence of inflammation in COVID-19. Through experiments in the lab and with mice, the researchers show that blood clotting is instead a primary effect, driving other problems—including toxic inflammation, impaired viral clearance, and neurological symptoms prevalent in those with COVID-19 and long COVID.

“Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can build a new path forward for treating the disease at the root,” says Katerina Akassoglou, PhD, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. “In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection.”

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Katerina Akassoglou Receives 2024 Pharmacia-ASPET Award

Katerina Akassoglou, PhD, FASPET

ASPET is pleased to award Dr. Katerina Akassoglou, PhD from the University of California, San Francisco, the 2024 Pharmacia-ASPET Award for Experimental Therapeutics. This award recognizes outstanding research in pharmacology and experimental therapeutics, basic laboratory or clinical research that has had, or potentially will have, a major impact on the pharmacological treatment of disease.

Dr. Akassoglou is receiving this award in recognition of her work on neurovascular and neuroimmune mechanisms that will have a major impact on the treatment of neurological diseases.

Dr. Katerina Akassoglou has pioneered studies on neurovascular regulation of inflammation and tissue repair and the molecular interface blood proteins utilize to interact with nervous system cells. She developed a first-in-class fibrin-targeting immunotherapy, currently in Phase 1, for the treatment of neurological diseases. She has published over 100 papers and is an inventor on 11 issued and several pending patents. She was awarded by the White House the Presidential Early Career Award for Scientists and Engineers, the John J. Abel Award in Pharmacology, the Dana Foundation and Marilyn Hilton Awards, the Barancik and ISFP Prizes and she was named by the San Francisco Business Times among the 2021 Most Influential Women in Bay Area Business. She is a Fellow of the American Neurological Association, an elected Fellow of the National Academy of Inventors, the American Association for the Advancement of Science and ASPET. She has been a member of ASPET since 2005.

A New Therapeutic Target for Traumatic Brain Injury

Jae Kyu Ryu, left, and Zhaoqi Yan, right, collaborate in the Gladstone lab of Katerina Akassoglou.

The glaring absence of treatments for such a widespread condition drove a team of scientists at Gladstone Institutes to uncover, on a molecular level, how traumatic brain injuries trigger neurodegeneration—and just as importantly, how to target that process to prevent long-term damage.

“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,” says Jae Kyu Ryu, PhD, a scientific program leader in the lab of Katerina Akassoglou, PhD, at Gladstone Institutes.

Most traumatic brain injuries come as a result of falls, car crashes, or violent assaults, according to the Centers for Disease Control, but many also stem from sports accidents or certain military operations such as explosions. In each case, the external force is strong enough to move the brain within the skull, causing a significant breakdown in the blood-brain barrier and allowing blood to move in.

“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,” says Ryu, who led the study that appears in the Journal of Neuroinflammation.

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How Blood That Leaks into the Brain Makes Immune Cells Toxic

“Our study answers, for the first time in a comprehensive way, how blood that leaks into the brain hijacks the brain’s immune system to cause toxic effects in brain diseases,” said Akassoglou, who is also director of the Center for Neurovascular Brain Immunology at Gladstone and a professor of neurology at UC San Francisco (UCSF). “Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases.”

Read the full article here.

Revealing How Blood Triggers Brain Disease

In patients with neurological diseases like Alzheimer’s disease and multiple sclerosis, immune cells in the brain known as microglia that normally fulfill beneficial functions become harmful to neurons, leading to cognitive dysfunction and motor impairment. These harmful immune cells may also contribute to age-related cognitive decline in people without dementia.

Read more here.

 

 

Nature Immunology Selected Our Image For The July 2023 Volume 24 Cover

Katerina Akassoglou and colleagues provide single-cell RNA-sequencing and phosphoproteome analyses of CNS microglia and macrophages in response to blood proteins including activated complement and fibrin. Their findings point to potential therapeutic targeting of microglia activation by immune and vascular signals.

Therini Bio Initiates First-In-Human Dosing in Phase 1 Trial of THN391, a Fibrin-Targeting Therapeutic Candidate for Alzheimer’s Disease

Therini Bio, Inc., a biotech company focused on developing fibrin-targeted therapies to treat inflammatory neurodegenerative and retinal diseases, today announced the initiation of first-in-human dosing for a Phase 1 trial of its lead asset THN391, a fibrin-targeting therapeutic candidate for Alzheimer’s disease.

Read the full article here.

Exclusive: Therini raises $36M, will target fibrin protein for Alzheimer’s and diabetic macular edema

Therini Bio has raised a $36 million Series A and will head to the clinic with an antibody that neutralizes fibrin, a blood clotting protein, that it hopes could have broad applications in tamping down inflammation.

Read more here.

Our Chapter Was Selected For The Alzheimer’s Disease Book Cover

The laboratory of Dr. Katerina Akassoglou developed a method for three-dimensional imaging of neurovascular alterations and blood-brain barrier disruption in cleared human brains. The image shows fibrin (red) around damaged blood vessels (green) and amyloid (blue) in the brain from a patient with Alzheimer’s disease.

Image Credit: Mario Merlini