(From Pediatric Directions, Issue 38)
The Research Institute at Nationwide Children’s continues to rank in the top 10 among all freestanding pediatric research organizations based on NIH funding. In 2010, The Research Institute received $69.4 million in external funding, $37.3 from the National Institutes of Health. Now there are more than 900 IRB-approved protocols in progress.
The Research Institute faculty and staff include:
In the past decade, the number of faculty scientists at The Research Institute has nearly quadrupled, with “Research Building III” scheduled to open shortly after the new main hospital in 2012. With this new expansion, Nationwide Children’s will be home to one of the fastest growing pediatric research centers in the United States.
Dr. Besner Receives RO1 Grant to Continue NEC Research
Gail E. Besner, MD, Department of Surgery, and member of the Center for Perinatal Research at The Research Institute has been awarded a 4-year RO1 grant from the National Institutes of Health (NIH) to continue work on HB-EGF and Intestinal Reperfusion to treat the disease process known as necrotizing enterocolitis (NEC). This award represents years 9 through 12 of this innovative project. As a translational researcher, in addition to her work at the bench, Dr. Besner is also a cutting-edge clinical surgeon and residency training program director. Besner’s laboratory has achieved a level of NIH funding and international acclaim that places it among the very top surgical laboratories in the world.
Dr. Besner and researchers in her lab have learned that HB-EGF can protect the intestine from several forms of injury, based on experiments performed at the cell biology, molecular biology and whole animal levels. They believe that this growth factor may protect the intestines of premature infants from the life-threatening injury caused by NEC. The goal of Dr. Besner’s work is the prophylactic and therapeutic treatment of high-risk neonates using HB-EGF, in order to prevent and treat this often devastating disease.
Dr. Besner, who is also the John E. Fisher Endowed Chair in Neonatal Research, a professor of Surgery and Pediatrics at The Ohio State University College of Medicine, and co-director of the Burn Program at Nationwide Children’s, has diligently pursued this work at Nationwide Children’s for 20 years. Her achievements are leading to discoveries that will positively influence lives all over the world.
NIH Grant Used to Implement First Clinical Trial with Drug to Prevent Infection in Critically Injured Children
Nationwide Children’s will be the first to implement a clinical trial aimed at improving immune function in critically injured children. Thanks to funding from the National Institutes of Health (NIH), researchers at The Research Institute at Nationwide Children’s will test the ability of a drug commonly used to improve immune function in pediatric cancer patients to help prevent hospital-acquired infection after severe trauma.
The leading cause of death for children outside the neonatal period is traumatic injury. Beyond the life-threatening damage caused by initial injury, traumatically injured children are at high risk of developing life-threatening nosocomial infection. The incidence of nosocomial infection is especially high in injured children who require treatment in the intensive care unit.
“Adult studies have shown that innate immune function, which is responsible for protecting the body by identifying and killing pathogens, is impaired following critical injury,” said Mark Hall, MD, Critical Care Medicine physician at Nationwide Children’s and principal investigator in the Center for Perinatal Research. “Using a unique immune surveillance approach at Nationwide Children’s, we have shown a similar finding in children and are able to tell, in a matter of hours, whether or not a child is at high-risk for developing nosocomial infection.” Dr. Hall’s studies have identified specific thresholds of immune function, by measuring the ability of patients’ blood to produce certain chemicals when stimulated outside the body that predict infection risk.
“Thanks to our studies, we have known for some time what level of immune function is associated with poor outcomes,” said Dr. Hall. “What has been missing is a possible intervention.” With funding from the National Institute of General Medical Sciences, Dr. Hall is set to lead a clinical trial to help determine whether granulocyte macrophage colony stimulating factor (GM-CSF), a drug commonly used to reconstitute bone marrow in leukemia and bone marrow transplant patients, could be the intervention needed to help protect critically ill children from infection. “Several small studies in adults suggest that GM-CSF can reverse critical-illness-induced immune suppression,” said Dr. Hall. “Ours is the first study to use this drug in critically injured children.”
Through the GIFT study (GM-CSF for Immunomodulation Following Trauma study), Dr. Hall will test whether GM-CSF can boost the immune system enough to reduce the risk for nosocomial infection after critical injury in high-risk children. After determining the lowest tolerable, yet effective dose, Dr. Hall’s team will test whether GM-CSF delivery can prevent nosocomial infection in children whose immune monitoring data designates them at high risk for infection. They will also perform a smaller version of this study in high-risk children who have severe traumatic brain injury.
Human-Cell-Derived Model of ALS Provides a New Way to Study the Majority of Cases
For decades, scientists have studied a laboratory mouse model that develops signs of the paralyzing disease amyotrophic lateral sclerosis (ALS) as they age. In a new study appearing in Nature Biotechnology, investigators at Nationwide Children’s Hospital have developed a new model of ALS, one that mimics sporadic ALS, which represents about 90 percent of all cases.
ALS, commonly known as Lou Gehrig’s disease, is characterized by the death of motor neurons. As these neurons die, the body’s voluntary muscles weaken and waste away; death within five years of diagnosis is common. Only about 10 percent of ALS cases are familial. The majority of ALS cases are sporadic, with no family history. Mutations in the SOD1 gene are found in about one-fifth of people with familial ALS, and for decades, experts have theorized that the gene holds clues to sporadic ALS. Laboratory mice carrying human SOD1 mutations develop signs of ALS as they age, and have been widely used to investigate the causes and potential treatments for the disease. At the same time, however, researchers have questioned whether SOD1 mice are useful and whether SOD1 itself is relevant for understanding sporadic ALS. While dozens of potential therapies have shown promise in the mice, most have failed in patients.
“The mouse models capture a type of familial ALS that accounts for only two percent of all cases. The field has begged for new disease models that can provide a clear window into sporadic ALS,” said senior author Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy of The Research Institute at Nationwide Children’s. Nationwide Children’s researchers attempted to develop such a model by isolating cells from patients’ spinal tissue within a few days after death.
First, the team isolated neural progenitor cells from post-mortem spinal tissue of patients with ALS. Neural progenitor cells are the “parent” cells of neurons and astrocytes, cells of the central nervous system. They then coaxed these progenitor cells to develop into astrocytes. Next, the team combined the patient-derived astrocytes with mouse motor neurons. At first, the motor neurons grew normally, but after four days, they began to degenerate. By five days, the number of motor neurons reduced by about half compared to motor neurons that had been grown with control astrocytes. Similar results were seen when the motor neurons were grown with astrocytes from a patient with familial ALS, or with a cell culture broth that had been conditioned by astrocytes from any of the ALS patients. This suggests the ALS-derived astrocytes are releasing one or more unknown toxins.
Further experiments revealed that inflammatory responses and SOD1 may play a critical role in this toxicity. These results suggest that replacing astrocytes may be just as important as replacing motor neurons lost to the disease and that astrocytes and SOD1 need further investigation as targets for therapy.
“It has been a long road, but the hard work starts now,” said Dr. Kaspar. “We still need to confront fundamental questions about what is happening to astrocytes and how they are killing motor neurons. And the ultimate goal is to identify therapies that will translate into helping humans.”
Haidet-Phillps AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhites S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammescheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK. “Astrocytes from familial and sporadic ALS patients are toxic to motor neurons.” Nature Biotechnology, 2011 Aug; 29(9): 824-8.