The use of CR2Crry to reduce the negative effects of brain hemorrhage in preterm infants

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

Many of these babies are born prematurely, at 30 weeks of age or less, and have a high chance of developing a hemorrhage in their brain soon after birth, known as germinal matrix hemorrhage (GMH). Bleeding like this into the brain substance is a form of stroke that can lead to a buildup of fluid in the brain known as hydrocephalus — both of which put children at increased risk of neurodevelopmental disability, many of which do not survive.

There is currently no medical treatment for GMH, and since these blood vessels are more sensitive 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, read about the work that Stephen Tomlinson, PhD, vice chair of the Division of Microbiology and Immunology at MUSC, had been doing regarding a specific part of the immune system known as the complement system, he thought It may have applications for infants as well.

We just had to wait for bad things to happen. Then we had to answer them. We don’t have a cure for the actual bleeding or to prevent the stroke or hydrocephalus that comes next. Tomlinson was researching adult brain diseases, and we thought it would be a great opportunity to apply his methods to an animal model of premature babies.. “


Ramin Eskandari, MD, pediatric neurosurgeon, Medical University of South Carolina Health

as co-principal investigators of their recent paper in International Journal of Molecular Sciences, Tomlinson and Eskandari created a mouse model representing very low birth weight preterm infants and for treatment options for GMH. Dr. Mohamed Al-Sharif, a MUSC resident neurosurgeon and member of the Collaborative Laboratory, has discovered that by inhibiting the complement system at a specific site within the brain immediately after a hemorrhage, it can prevent many of the permanent and temporary disabilities that accompany hydrocephalus and stroke.

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

As part of the immune system, the complement system helps antibodies and phagocytes activate inflammation and remove microbes and damaged cells from the body, labeling and attacking them. But activating inflammation also leads to the harmful effects of GMH, and while there is still no way to prevent primary bleeding, Tomlinson and Eskandari are excited about the potential opportunity to prevent events that occur after brain hemorrhage.

Cases of GMH are on the rise, and according to Eskandari, this rise is actually due to better care and clinical advances. Thanks to improved prenatal care and better treatment options for premature babies, more babies are surviving premature birth. But with more survival, the chances of developing GMH increase.

“We are seeing younger and younger children who are able to survive,” Iskandari said. “I remember when a 23-week-old was unable to live, and even in the past eight years since my residency we now see 20-week-old babies who are not only viable, but live a full life and go to school.” It is these medical developments that show to Iskandari how important the results of this study are. And GMH treatment has the potential to change the course of an infant’s life.

Success in inhibiting the supplement regime has led to a boom in research recently, with more than 100 clinical trials currently underway, according to Tomlinson. But the CR2Crry inhibitor has its own niche. By specifically targeting treatment to the point where pathology begins, doctors do not need to completely disrupt the body’s complement system, which can increase the risk of infections and other immune disorders. They can use less inhibitor and direct it to a local site, which is safer for patients.

“It’s because this is targeted,” Tomlinson said. “We can actually inject fairly small concentrations directly into the bloodstream to target the affected brain.”

In addition to using the CR2Crry inhibitor to develop a new treatment for premature babies, Eskandari and Tomlinson believe it holds promise for treating other forms of brain injury as well. “These kids are a really good overall model of how all brain injuries are treated,” Eskandari said. “Bleeding that leads to stroke and hydrocephalus checks a lot of the boxes that we see in a lot of patients.”

Tomlinson’s future research plans include looking at the supplement regimen at various points after injury in an effort to understand the point at which it becomes part of the pathology of the injury rather than part of the healing process.

Iskandari 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 as fully as possible. “We want to allow these children to reach their full potential,” he said.

source:

Medical University of South Carolina

Journal reference:

Sharif, M. and others. (2022) The role of complement in the pathological consequences of germline matrix hemorrhage in the neonatal mouse. International Journal of Molecular Sciences. doi.org/10.3390/ijms23062943

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