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Fetal brain a focus of NIH project study If innovative clinical therapies, cures and treatments for patients are the light at the end of a long tunnel, then collaborative research and interdisciplinary cooperation are the steam engine and tracks that will get them there.     In recent months, the Darby Children’s Research Institute (DCRI) achieved numerous advances in the name of collaborative research, including a $1.9 million-grant to investigate a strategy initially proposed by Inderjit Singh, Ph.D., professor of pediatrics, director of the Division of Developmental Neurogenetics and DCRI research director.   The National Institutes of Health (NIH) awarded the three-year pilot project grant to principal investigator Doe Jenkins, M.D., neonatologist, to protect the brains of children still in the womb from damage by an infection called chorioamnionitis. Jenkins conducted previous research on the prevention of neonatal brain injury after hypoxic-ischemic injury, and began to collaborate with Singh to develop a program to reduce neonatal inflammation. The effort progressed quickly from the realm of bench research into a grant proposal for an investigational clinical pilot trial.   “We feel that this study could be ground breaking in establishing a new form of clinical intervention (anti-inflammatory and anti-oxidant) for pregnant women,” said Roger Newman, M.D., a co-investigator from the Department of Obstetrics and Gynecology for the new pilot study.   Jenkins’ study will build upon Singh’s basic science discoveries made in DCRI testing whether giving N-acetylcysteine (NAC) to pregnant women with a chorioamnionitis infection can decrease their baby’s baseline level of brain inflammation and improve the fetal tolerance of labor and delivery. Ultimately, researchers hope to find that NAC will result in less injury to the brains of the unborn babies.   “We’ve found a lot of stuff we didn’t expect to find,” said Eugene Chang, M.D., co-principal obstetric investigator. “We’re very convinced NAC is safe and hope this will lead to more research down the road. Ultimately, we hope it will prevent some cases of cerebral palsy.”   The study is part of an overall effort at MUSC to reduce brain damage and neonatal mortality, according to Lyndon Key, M.D., Department of Pediatrics chairman.   “The watchword for the Darby CRI has always been collaboration, and as MUSC prepares to apply for a Clinical and Translational Sciences Award, our successes through teamwork are right on target. These projects are bringing together investigators from a variety of fields to form departmental and institutional collaborations to attack health concerns in a way that could never be done through individual study. We are that much closer to overcoming many of them.” Laying the tracks Setting things in motion for the large NIH grant were suggestions from Key and Singh that neuroprotection agents such as NAC could prevent perinatal brain injury in a variety of diseases in neonates.   Basic science work on behalf of Singh, Chang and Ernie Barbosa, M.D., Neurology, supported these ideas. Their work in animal models showed that within hours of the umbilical cord becoming infected, the fetal animal brain had evidence of inflammation due to infection from the mother. When it was time to give birth, blood flow from the umbilical cord was periodically interrupted as a part of the natural process, but this was devastating for the fetal brain rampant with infection. The study showed that not only would the infant probably have infection-related brain damage, but the birthing process could make that damage worse. “We have long known that term and preterm infants who are exposed to infection (chorioamnionitis) in labor—or even [exposed] just to maternal fever—are at greater risk of neurological injury up to and including cerebral palsy, despite prompt initiation of antibiotics on delivery,” Newman said.   When Singh and his colleagues tested their hypothesis, they found a reduction in the level of inflammatory damage in the brains of animals with chorioamnionitis as a result of using NAC. They published these findings in the Journal of Neuroscience Research in November 2004.   Using the animal data from that study, Jenkins and her colleagues developed a clinical pilot proposal that would provide pregnant women with NAC to prevent fetal brain inflammation that accompanies chorioamnionitis infection, which can result in conditions such as cerebral palsy.   “It’s a new and innovative approach which we’ve developed as a collaborative group involving bench and clinical researchers from five different departments,” Jenkins said. “Everyone’s role is invaluable. This is a team of incredible people.   “We’ve been working for about two years with Epidemiology and Biostatistics, Pediatric Radiology, Obstetrics, and with pharmacologists to develop this protocol,” Jenkins continued. Fueling the engine Part of the study design requires complex pharmacological data with multiple dynamics to consider, including placental transport of NAC to the fetus at different gestation ages. “The complex, multi-compartment pharmacokinetic models are important to make sure fetal serum levels would not be in the toxic range and to allow us to test the effect of different doses of NAC safely,” Jenkins said. Although NAC has been used for decades to treat Tylenol overdose in pregnant women, there is little data on fetal levels. “Working together, we have come up with much more than we would have working in isolation,” she said.   With so many disciplines involved, the group was able to develop several approaches. For instance, the study will use magnetic resonance spectroscopy, or MRS, to detect NAC in baby brains. A good chance for Jenkins and her colleagues having received the grant was because of their innovative way to measure neuro-therapies in the brain.   The delivery of NAC is also unique in this case, because the mother is receiving the doses with the ultimate target being a certain level of NAC in the developing brain of the fetus prior to delivery. “This is a new area for neuro-protection, but to protect the infant’s brain from oxidative injury in chorioamnionitis, therapies may well have to be given antenatally to be effective,” she explained.   The study will monitor both baby and mother for possible side effects, gather pharmacological data for both preterm and near-term babies, measure NAC in the brain of infants after birth, and record responses to NAC in blood flow, cytokine levels and brain imaging.   Researchers expect to see that NAC decreases brain inflammation in a dose or concentration-dependent manner. If they show it’s effective in short-term outcomes, then they would prove long-term outcome effectiveness in a phase III trial. “It could be a safe and effective therapy for almost any mother with chorioamnionitis prior to delivery to help protect her baby’s brain,” Jenkins said. “NAC may prove to be one of only a few therapies for preterm babies that are both safe and neuro-protective.”   Conducting infant-related studies involves a huge collaborative effort and requires the type of NICU facility that currently is underway for MUSC Children’s Hospital. “Our challenge is to expand and improve neonatal/obstetric facilities and resources to support innovative investigations like this one,” said David Annibale, M.D., the neonatology division director.   “This is exactly the type of translational research that the institute’s benefactors and investigators hoped for. Now that everyone is hard at work in linking basic research findings to children’s diseases, we see the DCRI developing as a model for children’s research in the Carolinas and nationwide,” said Bernie Maria, M.D., DCRI executive director.     Friday, Oct., 27, 2006 Catalyst Online is published weekly, updated as needed and improved from time to time by the MUSC Office of Public Relations for the faculty, employees and students of the Medical University of South Carolina. Catalyst Online editor, Kim Draughn, can be reached at 792-4107 or by email, catalyst@musc.edu. Editorial copy can be submitted to Catalyst Online and to The Catalyst in print by fax, 792-6723, or by email to catalyst@musc.edu. To place an ad in The Catalyst hardcopy, call Island Publications at 849-1778, ext. 201.