Offer a potential treatment option to the inf

image: By treating GMH mouse models with the complement inhibitor known as CR2Crry, Tomlinson and Eskandari found improved survival and weight gain, reduced brain damage and incidence of hydrocephalus, as well as improved motor and cognitive performance in adolescence.
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Credit: Anne Thompson

Just over 1% of babies born in the United States in 2020 were in the very low birth weight category, meaning they weighed less than 1,500 grams at birth or 3 pounds and 4 ounces. And given that the Centers for Disease Control and Prevention says more than 3.5 million babies were born that year, almost 48,500 were considered to have very low birth weight.

Many of these babies are born premature, at 30 weeks or less, and they have a high risk of having a brain hemorrhage soon after birth, known as a germinal matrix hemorrhage (GMH). Such bleeding into the substance of the brain is a form of stroke that can lead to a buildup of fluid in the brain called hydrocephalus – which puts babies at increased risk of neurodevelopmental disability, and many do not survive.

There is currently no medical treatment for GMH, and because these blood vessels are even more delicate when a baby is born prematurely, there is no way to predict or prevent bleeding in the brain after birth.

When Ramin Eskandari, MD, a pediatric neurosurgeon at MUSC Health, learned about work that Stephen Tomlinson, Ph.D., vice chair of MUSC’s Department of Microbiology and Immunology, was conducting on a specific part of the immune system known in as a complement system, he thought it might also have applications in infants.

“We just had to wait for bad things to happen,” Eskandari said. “And then we had to react. We have no treatment for the hemorrhage itself or to prevent the stroke or hydrocephalus that follows. Tomlinson was looking at adult brain pathologies, and we thought this would be a great opportunity to apply his methods to an animal model for premature infants.

As co-principal investigators for their recent article in the International Journal of Molecular Sciences, Tomlinson and Eskandari created a mouse model to represent very low birth weight preterm infants and to find treatment options for GMH. Mohammed Alshareef, MD, senior neurosurgical resident at MUSC and a member of the collaborative lab, found that by inhibiting the complement system at a specific site in the brain immediately after hemorrhage, they could prevent many of the permanent and temporary deficits that accompany hydrocephalus and stroke.

By treating GMH mouse models with the complement inhibitor known as CR2Crry, Tomlinson and Eskandari found improved survival and weight gain, reduced brain damage and incidence of hydrocephalus, as well as improved motor and cognitive performance in adolescence.

As part of the immune system, the complement system helps antibodies and phagocytic cells to activate inflammation and remove microbes and damaged cells from the body, marking and attacking them. But activating inflammation also leads to the damaging effects of GMH, and while there’s still no way to prevent the initial hemorrhage, Tomlinson and Eskandari are excited about the potential opportunity to prevent the events that occur after cerebral bleeding.

Cases of GMH are on the rise, and according to Eskandari, this increase is actually due to better care and clinical advancements. With improved prenatal care and better treatment options for premature babies, more babies are surviving by being born early. But with more survival, comes more chance of GMH.

“We’re seeing younger and younger viable babies,” Eskandari said. “I remember when a 23 week old baby was not viable, and even in the last eight years since my residency, we are now seeing babies at 20 weeks not only being viable, but living fully and going to school. .” It is these medical advances that show Eskandari how important the results of this study are. And treating GMH has the potential to alter the course of an infant’s life.

The success of complement system inhibition has led to a recent research boom, with more than 100 clinical trials currently underway, according to Tomlinson. But the CR2Crry inhibitor has its own niche. By targeting therapy specifically at the point where the pathology begins, doctors do not need to turn off the complement system throughout the body, which can lead to an increased risk of infections and other immune disorders. They can use less inhibitor and target it to a local site, which is safer for patients.

“It’s because it’s targeted,” Tomlinson said. “We can actually inject fairly low concentrations directly into the bloodstream to target the injured brain.”

As well as using the CR2Crry inhibitor to develop a new therapy for premature babies, Eskandari and Tomlinson believe it also holds promise for treating other forms of brain damage. “These babies are a really good overall model of how all brain damage could potentially be helped,” Eskandari said. “Having a hemorrhage that leads to stroke and hydrocephalus checks a lot of the boxes that we see in a lot of patients.”

Future research plans for Tomlinson include examining the complement system at different times after injury in an effort to better understand when it becomes part of the pathology of an injury rather than part of its healing process. healing.

Eskandari hopes to host human clinical trials with the human equivalent of the CR2Crry inhibitor at MUSC next. He wants to help his premature patients live the fullest life possible. “We want to allow these babies to reach their full potential,” he said.

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About MUSC

Founded in 1824 in Charleston, MUSC is home to the oldest medical school in the South as well as the state’s only integrated academic health sciences center, with a unique charge of serving the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and nearly 800 residents in six colleges: dentistry, graduate studies, health professions, medicine, nursing and pharmacy. MUSC provided more than $271 million in biomedical research funding in fiscal year 2020, continuing to lead the state in securing funding from the National Institutes of Health, with more than $129.9 million of dollars. For more information on academic programs, visit musc.edu.


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About Antoine L. Cassell

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