The Sherman Prize: Scott Snapper, MD

Sherman Prize winner Dr Scott Snapper reviewed his team's work on the genetics associated with IBD in children from the Open Air Studio at the Advances in IBD annual meeting. 

Scott Snapper, MD, is chief of the Division of Gastroenterology, Hepatology and Nutrition at Boston Children's Hospital and professor of pediatrics at Harvard Medical School. 

TRANSCRIPT:

Good morning. My name is Scott Snapper. I'm from Boston Children's Hospital and I am so honored today to receive the Sherman Prize. I'm humbled to be part of an extraordinary group of prior winners and especially excited to be here today with cowinner Michael Kappelman, another pediatrician, from UNC and Oriana Damas from the University of Miami.

Thank you to Bruce and Cynthia Sherman for establishing a prize with the sole mission that will inspire and have rippling effects for our community to bring us all closer to a cure for those suffering from inflammatory bowel disease.

For me, the most meaningful aspect of this award was that the nomination was initiated unbeknownst to me at the time by one of my dear mentees, Dr. Lauren Collen, who inspires and teaches me in everyone in the division at Boston Children's Hospital daily. Indeed, my greatest professional reward outside of patient care is the excitement and achievements of my mentees.

For decades, we've been studying the mechanisms by which very young children get inflammatory bowel disease, many who have a single monogenic cause for their disease. Children that develop disease under the age of 6 are considered very early onset IBD. With the joint leadership of Aleixo Muise in Toronto and Christoph Klein in Germany, as well as many leading investigators around the globe, we established the Very Early Onset Inflammatory Bowel Disease Consortium about 10 years ago. Our hope has always been to both come up with molecular understandings of why these children get IBD and to develop precision therapies, but also to use findings in very early onset IBD as a roadmap for understanding and developing therapies for all inflammatory bowel disease.

There are now over 100 genes known to be causal of inflammatory bowel disease, and many of which were discovered by members of our consortium. Remarkably, the identification of some of these genes has led to precision therapies that we believe can be leveraged to subgroups of patients with adolescent or adult onset inflammatory bowel disease.

Remarkably, most cases still are unsolved and our group is employing transcriptional and proteomic signatures in combination with genomic data to identify causal variants. Our lab is actively functionally validating numerous IBD candidates, several of which are tied to precision therapies. This work is currently being led in my group in Boston by two outstanding junior faculty mentees, Dr Jodie and Dr. Lauren Collen. Excitingly, through our Very Early Onset IBD consortium, we've generated a single cell RNA sequencing dataset from over 200 unique individuals with very early onset IBD, yielding what we believe to be one of the largest single cell atlases for any GI disease to date. This analysis has been led by another talented junior faculty mentee, Dr. Vanessa Mitsialis. The Atlas is being leveraged to define the unique transcriptional signatures of individual monogenic IBDs, which then serve as transcriptional guideposts to inform mechanisms of disease in patients with non-monogenic disease and overlapping signatures.

Remarkably, Dr. Mitzialis has already employed this concept, identifying an IL-1 dependent pathway that signals through the transcription factor MEOC-1 in ulcers as an important driver of fibrosis, a finding identified in IL-10 receptor deficient patients, but found to be applicable to all IBD patients with ulceration. Another exciting area of ongoing work, potentially linking very early onset IBD to all IBD has been work spearheaded by Dr. Lauren Collen in our group. She discovered a cohort of very early onset IBD patients who shared the clinical phenotype of severe infantile onset IBD refractory to multiple medications and a biochemical signature characterized by impaired STAT3 activation. Blood transcriptomics from these patients revealed a shared transcriptional signature characterized by markedly enriched IL-23 mediated signaling, prompting her hypothesis that these patients could be treated with IL-23 blocking therapies. All 4 patients treated with IL-12/23 blocking agents remarkably went into remission dramatically and rapidly.

Lauren is working to understand the molecular basis for disease in these patients and to scale this transcriptional signature as a biomarker of anti-IL-23 response and IBD more generally.

These are just a few areas of exciting work that we hope will move the needle forward towards precision therapy approaches for both very early onset IBD and IBD. Again, I want to thank Bruce and Cynthia Sherman for this remarkable honor of being a Sherman awardee. Thank you.