Collaborators Uncover Genetic Basis of Very Early Onset Inflammatory Bowel Disease

By Barbara Drosey

It’s easy to see how Marcella Devoto, PhD, and Judith Kelsen, MD, work so well together. Their work is imperative, but they also are quick to laugh while falling in and out of side conversations about their research in the sort of shorthand longtime collaborators enjoy.

Dr. Devoto is a researcher in the Division of Human Genetics and the Very Early Onset Inflammatory Bowel Disease (VEO-IBD) Program at Children’s Hospital of Philadelphia, as well as the lead principal investigator of a genomics project that aims to ultimately improve care for children with VEO-IBD with targeted, individualized therapy. The project, “An Integrative Approach to Understanding the Genetic Basis of Very Early Onset Inflammatory Bowel Disease,” received funding support from the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK).

Dr. Devoto, who is also a professor of Pediatrics, Genetics, and Epidemiology at Perelman School of Medicine at the University of Pennsylvania, is already deeply involved in this work along with her mentee and colleague Dr. Kelsen who, as director of the VEO-IBD program, bestrides the worlds of research and hands-on clinical care.

Together with their team of researchers, bioinformaticians, and molecular biologists, they are targeting a specific manifestation of a disease commonly seen in adults and older children, and that more often responds better to treatment in those patient populations. The symptoms of VEO-IBD are not as obvious as adult onset IBD, where typically the findings are diarrhea or abdominal pain or weight loss. Children may have blood in the stool, or they might just stop eating. They could have other signs, such as high fevers or infections, that don’t appear to be a problem with their intestine.

“The immediate goal is to rapidly identify what is causing the disease in the individual patient and start therapy, because this disease can be so severe, and has even led to fatalities,” Dr. Kelsen said. “There’s morbidity and the risk to the child, but also for the family, there’s a great burden of this disease.”

To aid in diagnosis, the team developed an IBD targeted sequencing panel that the VEO-IBD team helps analyze. As one of the largest IBD treatment centers in the United States, CHOP sees patients in all age ranges, and has successfully treated older patients. But VEO-IBD is distinguished by its severity in children up to 6 years of age, along with its refractory nature and resistance to existing therapies.

“We recognized a few years ago that these younger children weren’t responding to therapies the same way,” Dr. Kelsen said. “They had a more severe form of IBD and problems with their immune system that other patients didn’t have that prompted us to consider this could be a completely different disease: very early onset IBD.”

Curative Teamwork

As awareness of VEO-IBD grows, the number of patients the program is seeing in the clinic is skyrocketing. In 2013 the team saw approximately 20 new patients; by 2018 they had seen more than 90 new patients in one year. The team now follows over 650 patients in total and with their approach, they’re able to help patients earlier in the progression of their disease.

For these smallest patients with VEO-IBD, diagnosis and treatment has become more than identifying the disease and administering therapies. This unique multidisciplinary clinic includes gastroenterologists Dr. Kelsen, Máire Abraham Conrad, MD, MS, and Trusha Patel, MD; Kathleen Sullivan, MD, PhD, chief of immunology; Edward Behrens, MD, chief of rheumatology; and VEO-IBD nurses and research coordinators. The team aims to understand the exact cause of the problem and solve for a novel approach that combines gene sequencing, functional studies, and microbiome data to detect the genetic variants responsible for VEO-IBD, leading to targeted, effective, personalized therapies.

“Our program is both clinical and scientific, the exact definition of translational research,” Dr. Kelsen said.

The team collaborates with researchers throughout CHOP and Penn to investigate patients’ genetics for underlying causes of VEO-IBD. Dr. Kelsen estimates that 90 percent of the program’s current research focus is on new genes that have not been previously described. They use a variety of technology to expedite their search such as whole exome sequencing (WES), which is the focus of Dr. Devoto’s current grant.

Whole exome sequencing helps narrow the search field for genetic mutations from three billion nucleotides to approximately 30 million. Although exomes comprise a relatively small part of the human genome — just 1.5 percent — this is where 85 percent of mutations affecting rare monogenic diseases may be found. Helping to sort through the sequencing results is Noor Dawany, PhD, bioinformatics scientist in the VEO-IBD Clinic.

“That we have a dedicated senior bioinformatician with an understanding of biology and informatics is a really unique part of our program,” Dr. Kelsen said. “Dr. Dawany has developed amazing pipelines which allow us to go through the variants and determine which are potentially disease-causing. Some genes occur in only one patient, but what we learn about that one gene might teach us about a whole pathway that’s never been described; when we recognize a gene of that pathway in another patient, we know it’s relevant. Even if it’s only one gene per cohort, we might learn so much from that one gene to help other children.”

Identifying that sometimes elusive mutated gene is the crux of the new NIDDK grant, but Drs. Devoto and Kelsen agree it’s not the WES technology that makes their program special. It’s the ability to pull together a multidisciplinary team and communicate so effectively between the clinical and research staff to conduct successful collaborative research.

For example, if the team pinpoints a genetic mutation in a child’s exome, then they do routine biopsies and endoscopic procedures. They send those samples to Kathryn Hamilton, PhD, a researcher in the Center for Pediatric Inflammatory Bowel Disease, to grow into an enteroid culture. The enteroid is an accurate model that allows researchers to recapitulate the mutation and study the molecular pathogenesis of the disease. At the same time, Dr. Sullivan’s laboratory performs extensive work to understand the immune system in the patients. Together, this builds the scientific evidence needed to demonstrate a causative genetic effect in genes never before associated with VEO-IBD.

Better Futures

Once researchers identify the genetic defect, then they can tailor the treatment. Sometimes a therapy already exists that can cure the patient; in other cases, a one-time, curative therapy can eradicate the disease.

“In 16 cases, we’ve identified a genetic cause that we know from prior experience will get better with a new immune system, and we’ve done stem cell transplants for these patients,” Dr. Kelsen said.

Along the way, the team is also learning more about older onset IBD by incorporating the same integrative approach utilized for younger children when adult centers send refractory cases to CHOP. 

“In the long run, we would like to see whether the same gene pathways responsible for the disease in these children will also have an impact on the adult population,” Dr. Devoto said. “While the disease looks different in many cases, sometimes you learn lessons from the rare, severe cases that can also be applied to more common, less-severe phenotypes.”

Buoyed through funding from CHOP’s Frontier Programs initiative, the IBD Program team will continue to bridge science and clinical care for innovative outcomes.

“There’s still a lot we don’t understand,” Dr. Devoto said. “We have all these ‘candidates,’ as we call them, that come out of the genetic analysis and the bioinformatic analysis. We look forward to expanding the program to be able to follow up on all of that.