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newborn in incubator

How EPO saves babies’ brains

newborn in incubator

Researchers have discovered that treating premature infants with erythropoietin can help protect and repair their vulnerable brains.

The drug erythropoietin (EPO) has a long history. First used more than three decades ago to treat anemia, it’s now a mainstay for treating several types of this blood-depleting disorder, including anemia caused by chronic kidney disease, myelodysplasia and cancer chemotherapy.

More recently, researchers discovered a new use for this old drug: Treating premature infants to protect and repair their vulnerable brains. However, how EPO accomplishes this feat has remained unknown. New genetic analyses presented at the Pediatric Academic Societies 2018 annual meeting that was conducted by a multi-institutional team that includes researchers from Children’s National show that this drug may work its neuroprotective magic by modifying genes essential for regulating growth and development of nervous tissue as well as genes that respond to inflammation and hypoxia.

“During the last trimester of pregnancy, the fetal brain undergoes tremendous growth. When infants are born weeks before their due dates, these newborns’ developing brains are vulnerable to many potential insults as they are supported in the neonatal intensive care unit during this critical time,” says An Massaro, M.D., an attending neonatologist at Children’s National Health System and lead author of the research. “EPO, a cytokine that protects and repairs neurons, is a very promising therapeutic approach to support the developing brains of extremely low gestational age neonates.”

The research team investigated whether micro-preemies treated with EPO had distinct DNA methylation profiles and related changes in expression of genes that regulate how the body responds to such environmental stressors as inflammation, hypoxia and oxidative stress.  They also investigated changes in genes involved in glial differentiation and myelination, production of an insulating layer essential for a properly functioning nervous system. The genetic analyses are an offshoot of a large, randomized clinical trial of EPO to treat preterm infants born between 24 and 27 gestational weeks.

The DNA of 18 newborns enrolled in the clinical trial was isolated from specimens drawn within 24 hours of birth and at day 14 of life. Eleven newborns were treated with EPO; a seven-infant control group received placebo.

DNA methylation and whole transcriptome analyses identified 240 candidate differentially methylated regions and more than 50 associated genes that were expressed differentially in infants treated with EPO compared with the control group. Gene ontology testing further narrowed the list to five candidate genes that are essential for normal neurodevelopment and for repairing brain injury:

“These findings suggest that EPO’s neuroprotective effect may be mediated by epigenetic regulation of genes involved in the development of the nervous system and that play pivotal roles in how the body responds to inflammation and hypoxia,” Dr. Massaro says.

In addition to Dr. Massaro, study co-authors include Theo K. Bammler, James W. MacDonald, biostatistician, Bryan Comstock, senior research scientist, and Sandra “Sunny” Juul, M.D., Ph.D., study principal investigator, all of University of Washington.

The search for precise blood biomarkers of neonatal brain injury

Bloodbiomarkers

What’s Known:
Hypoxic-ischemic encephalopathy (HIE) is characterized by reduced blood and oxygen flow to a baby’s brain around birth and may cause neurologic disability or death. It occurs most commonly after intrauterine asphyxia brought on by such difficulties as circulatory problems, placental abruption, or inflammatory processes. Newborns with HIE may suffer seizures, difficulty feeding, and disturbed control of heart rate and breathing. Cooling therapy, which is the standard of care, offers some protection to the developing brain, but up to 50 percent of HIE-affected infants still have poor outcomes.

What’s New:
Research scientists at Children’s National Health System are involved in a multi-center clinical trial to determine if erythropoietin (EPO), a hormone naturally secreted by the kidneys and commonly used to treat anemia, helps to prevent brain injury in these infants. The trial, called the HEAL Study (High Dose Erythropoietin for Asphyxia and Encephalopathy), is exploring whether EPO, given in addition to hypothermia, further lowers the risk of brain injury in HIE-affected babies. As a part of this study, researchers at Children’s National are leading the investigation to identify biomarkers of brain injury. Biomarkers are telltale chemicals in the blood and are used in tests that evaluate whether patients have suffered a heart attack. While available biomarkers warn when the heart, kidney, or liver is in trouble, there is no blood biomarker that signals ongoing brain injury. Such blood biomarkers could help to determine which infants are responding to treatment as well as to precisely identify which HIE-affected infants are still struggling and require additional treatments, such as EPO, to protect the brain and improve outcomes.

Questions for Future Research: 

  • Does EPO, in tandem with hypothermia, improve long- term neurodevelopmental outcomes in newborns with HIE?
  • Which biomarkers, or panel of biomarkers, best reflect the timing and severity of neonatal brain injury?
  • Can biomarkers direct which types of treatments are best for specific patients and when they should be used?

Source: Plasma Biomarkers of Brain Injury in Neonatal HIE (Hypoxic-Ischemic Encephalopathy).” A.N. Massaro, Y. Wu, T.K. Bammler, A. Mathur, R.C. McKinstry, T. Chang, D.E. Mayock, S. Mulkey, K. Van Meurs, L. Dong, R. Ballard, and S. Juul. Presented during the 2016 Pediatric Academic Societies Annual Meeting, Baltimore, MD. May 3, 2016.