Frontiersmen historically are a rare breed of adventurers willing to brave the unknown in order to discover new paths. The physician-researchers who are leading new Frontier Programs at Children’s Hospital of Philadelphia embody this pioneering spirit as they forge ahead to help children achieve optimal health and better lives.
The Frontier Programs initiative at CHOP designates funding to large internal programs that connect translational research and clinical care in extraordinary ways. This spring, 19 programs applied, and after a rigorous review process, the oversight panel selected two outstanding programs: the Thoracic Insufficiency Syndrome (TIS) Program and the Inflammatory Bowel Disease (IBD) Program.
Breathing Easier: Thoracic Insufficiency Syndrome Program
TIS encompasses a group of at least 28 rare and potentially fatal disorders in which spinal and chest wall deformities early in life compromise children’s lung growth and ability to breathe. Robert Campbell, MD, director of the Center for Thoracic Insufficiency Syndrome (CTIS) at CHOP and an attending surgeon, invented the first FDA-approved Vertical Expandable Prosthetic Titanium Rib (VEPTR device) that enables surgical reconstructive procedures to enlarge these children’s rib cages and help to correct scoliosis to increase their chances of lung growth.
As VEPTR has become the standard of care for treating TIS, CTIS has treated more patients and more acute cases from all over the world and increased surgical volume for patients with TIS by an average of 15 percent every year since 2012 at CHOP. The need for more TIS research has grown along with the Center.
Being named a Frontier Program will allow Dr. Campbell and a multidisciplinary team of specialists to perform sophisticated imaging, construct new metrics for clinical outcomes, better understand the biomechanics of TIS, and establish reliable evidence to support new surgical strategies and develop new medical devices.
“The Frontier funding supports programs that are clinically robust and have the potential for rapid advancement,” Dr. Campbell said. “It’s like getting a turbo charger. It’s hard to win the race if you don’t have one.”
CTIS hit the starting line with about 20 research projects that are underway. For four years, Dr. Campbell and his colleagues have collaborated with Jayaram Udupa, PhD, a professor of Radiologic Science from the University of Pennsylvania Department of Radiology Medical Image Processing Group, to develop dynamic lung magnetic resonance imaging (dMRI) image analysis as a way to measure thoracic performance — which is how well the thorax, spine, and rib cage work in combination — before and after surgical intervention for TIS. The research team will refine and scientifically validate this new assessment technique in correlation with pulmonary function.
In order to get a complete view of the anatomy in these unusual diseases that the CTIS treats, the research team also collaborates with Sriram Balasubramanian, PhD, an associate professor in the School of Biomedical Engineering, Science and Health Systems at Drexel University, to perform detailed software analysis of computed tomography (CT) scans of patients, which shows bone better than MRIs.
Together, these approaches will be the basis for the CTIS’ advanced imaging research program. One of the investigators’ first projects is called the Virtual Growing Child, which will help to establish normative data for comparative analysis. Quantifying the degree of dysfunction in the rib cage and diaphragm will provide a new metric to define thoracic performance in TIS.
CTIS also is launching a basic science lab that will establish an animal model of TIS. Casey Olson, PhD, a medical bioengineer who recently joined the CTIS team, will be leading this research to better understand at an anatomic level how expanding these children’s chests promotes lung growth. This biological platform will help them to develop new devices and surgical methods that closely mimic thoracic function to treat TIS.
As this body of research forms the scientific basis for TIS surgical interventions, Dr. Campbell also is excited to pursue studies that focus on patients’ and families’ quality of life outcomes. Measuring these surgeries’ success goes beyond if the MRI and CT images look better, he pointed out. Many children who receive VEPTR devices are no longer dependent on oxygen support or mechanical ventilators. When these children can breathe easier, so can their parents, in many ways.
Dr. Campbell shared the example of a mother who had been sleeping every night at her son’s bedside so that she could suction him if he became congested or had mucus plugs in his lungs. As the surgery slowly allowed her son’s lungs to expand and move, he became more comfortable and could sleep through the night — and so could mom in her own bed.
“After treatment, these children feel better, are happier,” Dr. Campbell said. “They gain weight. They don’t go to the emergency room or intensive care unit as much, and they recover faster from illnesses. We don’t measure those type of things yet, but the Frontier funding will make it possible. We’re very appreciative of this. There are so many innovations at CHOP just waiting to happen.”
Making it Personal: Inflammatory Bowel Disease Program
Frontier funding will expand pediatric IBD care and research at CHOP, as an inventive multidisciplinary team takes a new approach that combines genomics and microbiome analysis to fulfill an unmet need for improved diagnostic modalities and therapeutics. IBD is a chronic autoimmune disease that includes Crohn disease and ulcerative colitis, and it has been rapidly increasing in incidence — especially among young children — mostly likely due to a complex combination of genetic and environmental factors.
The Center for Pediatric Inflammatory Bowel Disease at CHOP is the largest of its kind in the country, providing care for more than 1,400 children and adolescents. Under the combined leadership of Robert Baldassano, MD, and Andrew Grossman, MD, co-directors of the Center for Pediatric IBD; and Judith Kelsen, MD, a pediatric gastroenterologist and researcher; the Frontier program will increase the Center’s size and scope to provide the most advanced comprehensive care to pediatric patients with IBD from the U.S. and internationally. At the same time, their scientific observations will generate novel insights into pediatric IBD, which often is harder to treat than older-onset IBD, and can have dramatic consequences including poor growth, malnutrition, and the need for intravenous feeding and surgeries.
“The bottom line is we’re trying to improve the care of children who are suffering with this disease all over the world,” Dr. Baldassano said. “We believe that the model we are creating will be used at other institutions five or 10 years from now.”
At the heart of this model is CHOP’s ability to provide personalized medicine for children with IBD. Patients treated by the Center for Pediatric IBD undergo next-generation sequencing to identify the genetic defects that may underlie their disease. This not only aids diagnosis, but it also suggests which medications have the best chance of being effective. Another benefit is that it provides CHOP the opportunity to develop new gene-based therapies.
For example, previous research by Dr. Baldassano and his colleagues at the Center for Applied Genomics at CHOP discovered that many children with pediatric IBD and other autoimmune diseases have loss of function mutations in a specific immune regulatory protein that dampens inflammation caused by a pro-inflammatory protein called LIGHT. As part of a CHOP collaboration with industry partners that was announced in June, Dr. Baldassano will help to test a potential therapy that would be a first-in-class anti-LIGHT monoclonal antibody that binds excessive LIGHT to help control inflammation in pediatric patients with IBD.
The Center for Pediatric IBD also aims to move science forward by analyzing patients’ microbiome, which is the community of microbes that live on and within your body (the bulk of these organisms live in the gut) and contribute to numerous biological functions. Growing evidence supports the idea that the microbiome helps drive inflammatory bowel disease in people who are genetically predisposed.
In order to better understand the intestinal environment associated with IBD and characterize the disease more comprehensively, the Center for Pediatric IBD collects stool samples from IBD patients and uses next generation sequencing techniques available through the PennCHOP Microbiome Program, which Dr. Baldassano also codirects, to sequence hundreds of microorganisms’ genomes. The researchers will establish microbiota signatures of subsets of pediatric IBD, and then they will correlate these key communities of bacteria with patients’ genetic variants to help select the most appropriate therapeutic options.
“We believe the future of treating IBD will require us to combine the microbial information with the genetic information to figure out how the immune system is being manipulated by both,” Dr. Kelsen said. “Ultimately, we want to really understand the individual person’s disease to provide optimal therapy.”
The Center for Pediatric IBD team’s national leadership in clinical, translational, and basic research in IBD is exemplified by its expertise in treating very-early onset IBD (VEO-IBD), which is IBD that presents before age 5. Children with VEO-IBD are a unique part of the IBD patient population because they frequently present with more severe symptoms and greater extent of GI tract involvement than older children and adults with IBD. In addition, these patients tend to respond poorly to conventional IBD therapies used for older patients.
Research led by Dr. Kelsen identified some of the underlying genetic causes of VEO-IBD that may allow for targeted therapy in these children. These gene variants appear to influence the immune system and may result in defective or inappropriate immune responses that contribute to the development of VEO-IBD. For many of the patients who Dr. Kelsen sees in the VEO-IBD clinic that she runs with Kathleen Sullivan, MD, PhD, chief of the division of Allergy and Immunology, they are now using therapies that are directed to diseases of the immune system, instead of prescribing traditional IBD drugs.
Dr. Kelsen shared the inspiring story of a young infant with a form of IBD who spent four months in CHOP’s ICU being cared for by specialists from gastroenterology, immunology, and rheumatology who were committed to figuring out why she was so gravely ill. They discovered that she had a gene defect that caused an overwhelming inflammatory response. The team received compassionate use permission from the U.S. Food and Drug Administration to try an investigational drug that blocked that inflammatory process from happening. They recently described the patient’s case in the Journal of Allergy and Clinical Immunology.
“She went from an infant who was incredibly sick and couldn’t tolerate even an ounce of formula by mouth to a little girl who is now eating pizza and growing,” Dr. Kelsen said.
Dr. Kelsen and her colleagues expect to have many more success stories to tell, as the Center for Pediatric IBD at CHOP utilizes this multidisciplinary translational research approach to provide personalized therapy to more children worldwide. Already, they receive biospecimens from IBD patients nationally and internationally to perform sophisticated sequencing, analysis, and interpretation.
“We are incredibly excited,” Dr. Kelsen said. “This is an opportunity to provide better care and better science so that hopefully we can change the natural history of the disease.”