Researchers and pediatric gastroenterologists at four institutions, including Vanderbilt University Medical Center, were recently awarded a five-year, $9.4 million federal grant to tackle undiagnosed congenital diarrheas caused by a single gene mutation.
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awarded the funding for the Pediatric Congenital Diarrhea and Enteropathy (PediCODE) Consortium and Repository, which will consist of Vanderbilt — including the Departments of Surgery, Pediatrics and Cell and Developmental Biology, the Epithelial Biology Center and Monroe Carell Jr. Children’s Hospital at Vanderbilt — the University of California Los Angeles Department of Pediatrics, The Hospital for Sick Kids in Toronto and Boston Children’s Hospital.
In infants, severe, chronic diarrhea can cause dehydration and failure to thrive and has potentially life-threatening consequences. The team theorizes that genetic abnormalities in infants are the cause of many cases of undiagnosed congenital diarrhea, which is described as severe diarrhea that presents in the first two to four weeks of an infant’s life. In addition to the considerable health problems and the emotional toll on families, the health care cost burden is extremely high, sometimes translating into millions of dollars.
With an estimated 50% of all congenital diarrheas having no known etiology, PediCODE brings together a multidisciplinary group of physician-scientists with expertise in cell biology and genetic disorders. They are working to characterize the clinical and pathophysiological features of these diarrheas and develop a clinical database and biorepository of disease-specific cells, tissues and other primary patient materials.
Their focus will include identifying unknown gene mutations causing these diarrheas, studying the mechanisms behind both known and unknown genetic mutations and developing new ways to treat these diseases.
James Goldenring, MD, PhD, Paul W. Sanger Professor of Experiential Surgery, will serve as Vanderbilt’s principal site investigator and consortium co-principal investigator. Vanderbilt collaborators include Sari Acra, MD, MPH, chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition; Hernan Correa, MD, of Pediatric Pathology at Children’s Hospital; Joseph Roland, PhD, research associate professor of Surgery and managing director of the Digital Histology Shared Resource; and Matt Tyska, PhD, professor of Cell and Developmental Biology.
“We estimate that about 50% of congenital diarrhea disorders do not have an identified gene. Our major goal over the next five years is to make that number much smaller by identifying unknown genes that may be causing these congenital diarrheas. Also, for those genes that are known, we may know the defect and general structure, but we don’t know the mechanisms impacted by mutations,” said Goldenring.
“We have to identify the genes, and then as a team, especially if it’s a new gene, we have to dive into what’s functionally wrong with the cells, and we need to know if we have any chance of reversing or getting around the problem.”
With samples collected from each patient, the centers will perform or gather data from whole exome sequencing for many patients and develop a tissue histopathology atlas, or image database. The group will also store cell/biopsy samples that will be used to create intestinal organoids, or lab-created mini-guts that can be used to study the mechanisms behind the disorders and barriers to protein trafficking, and to test potential pharmacological therapies.
PediCODE also hopes to serve as an international research and clinical resource for children dealing with undiagnosed congenital diarrheas.
“We want to be a resource for other centers and gastroenterologists to help them get their patients on the right track,” said Acra. “Often, they can point the patient in the right direction, but because of inadequate resources or because the disorder has not been previously described, cannot make a definitive diagnosis. We can help overcome these barriers. Ultimately, we hope we can gain enough knowledge about these disorders to offer therapies that do not currently exist.”
PediCODE is funded under an RC2 grant (RC2DK118640) for high-impact, interdisciplinary science in NIDDK research areas. Other site principal investigators are Martin Marin, University of California Los Angeles, Aleixo Muise, MD, The Hospital for Sick Kids in Toronto, and Wayne Lencer, MD, Boston Children’s Hospital.
