PediCODE, a research consortium on congenital diarrhea and enteropathy, was recently awarded a five-year, $9.4 million grant to study the gene mutations behind congenital diarrhea in infants. Vanderbilt University Medical Center, the University of California Los Angeles Department of Pediatrics, the Hospital for Sick Children in Toronto, and Boston Children’s Hospital are collaborating on the research, funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
The goal is to characterize the clinical and pathophysiological features of the disease, identify unknown gene mutations, and develop a clinical database and biorepository of disease-specific cells and tissues.
“We estimate that about 50 percent 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,” said James Goldenring, M.D., Paul W. Sanger Professor of Experiential Surgery at Monroe Carell Jr. Children’s Hospital at Vanderbilt, and Vanderbilt’s principal site investigator. For previously characterized genes, the researchers plan to study mechanisms impacted by mutations.
“About 50 percent 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.”
“This is not a single disease,” added Sari Acra, M.D., division chief of pediatric gastroenterology, hepatology and nutrition, and a co-investigator on the study. “We expect to find multiple genetic causes with different manifestations. We need to first understand what’s functionally wrong with the cells involved and then look for adaptive or curative solutions.”
A Lifetime of Daily Dependency
Congenital diarrhea is rare, and in most cases there is no cure. The underlying etiology is often a conundrum to the treating physician, which can lead to a delayed diagnosis, misdiagnosis or inappropriate therapeutic strategies. “By the time the cause is diagnosed, the baby may already be in a downward spiral,” Acra said.
The disease threatens dehydration, electrolyte imbalances and malnutrition, leading to failure to thrive, and in some cases, mortality. Affected children typically face a lifetime of total parenteral nutrition. The cost of IV support and other medical expenses imposes a significant burden on caregivers and health systems.
Small bowel transplant is an option for some, but carries significant infection and rejection risks. For these reasons, Acra says it is reserved for cases where diarrhea is poorly controlled or parenteral access is limited by vein thrombosis from repeated feedings.
Targeting Gene Mutations
Congenital diarrhea is often idiopathic, though trafficking barriers caused by genetic mutations appear to be the constant. Much of the team’s work will focus on analyzing these genes. “When you do a genetic screen on a child, you’ll always see some mutations, but which ones fit the pathophysiology of the child’s diarrhea is the puzzle that we’re trying to figure out,” Acra said.
Through preclinical models, Goldenring and his collaborators have already identified ion transport deficits that commonly underlie the pathology of one of the known mutations, microvillus inclusion disease. They are now working on interventions.
In the new project, researchers will collect patient tissue samples and use whole exome sequencing to identify known or candidate mutations – producing a tissue histopathology atlas. They will also grow intestinal organoids from patient samples to recapitulate the specific disease. This will enable them to study mechanisms behind congenital diarrhea, as well as ways to restore normal electrolyte and nutrient trafficking.
The hope lies in finding therapies that either correct deficits or provide adaptive support to the patient. To foster this, the Vanderbilt team will use the organoid model to test potential drug or nutrient therapies.
“Since the cells involved are derived from the patient, we can readily test drugs on the organoids and quickly measure the impact.”
“Acting as mini-guts, organoids provide a particularly useful template for intestinal pathologies. Since the cells involved are derived from the patient, we can readily test drugs on the organoids and quickly measure the impact,” Acra said.
Acra cites cystic fibrosis research as an example of how identifying the mutation, the transport problem it caused, and a drug that corrects the nutrient delivery malfunction (in this case, chloride transport) dramatically changed the outlook for patients. “If we identify the congenital diarrhea mutations and the transport defects they create, we can find ourselves on a similar path,” he said.