Judy H. Cho, MD, Dean of Translational Genetics Director of The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai

Crohn’s Disease: Genetic and Cellular Mechanisms Identified

MedicalResearch.com Interview with:

Judy H. Cho, MD, Dean of Translational Genetics Director of The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai

Dr. Cho

Judy H. Cho, MD,
Dean of Translational Genetics
Director of The Charles Bronfman Institute for Personalized Medicine
Icahn School of Medicine at Mount Sinai

MedicalResearch.com: What is the background for this study? Would you briefly describe Crohn’s disease? Whom does it primarily affect?

Response: Crohn’s disease is a chronic inflammatory intestinal disease, which affects ~3 million Americans a year. Its most typical age of onset ranges from 15-30 years, and many of those diagnosed also exhibit frequent abnormal healing and complications that constrict the digestive tract. The highest risk genetic mutations that increase risk for Crohn’s disease are found in the gene NOD2; these were first reported 20 years ago. Biological mechanisms by which NOD2 mutations drive Crohn’s disease, and especially fibrotic complications, have been incompletely described up until this point. Further, the reasons why many patients fail to respond to the commonly administered anti-TNF treatments also remain incompletely understood.

MedicalResearch.com: What are the main findings?

Response: In this study we show that mutations in NOD2 drive an activated pathogenic signature via dysregulated myeloid and stromal cells. We analyzed inflamed and uninflamed intestinal tissues from Crohn’s disease patients, and zebrafish models of intestinal injury, and showed that these elevated signatures progress during disease pathogenesis, especially when NOD2 function is lost. In particular, we found an elevation of gp130-related gene expression, and that this was enriched in patients who do not respond to anti-TNF treatment. Given this finding, we show that blocking the protein gp130 can help reduce the pathogenic burden and could be a potential complementary therapeutic strategy to anti-TNF medications.

MedicalResearch.com: What should readers take away from your report?

Response: This work defines a completely new mechanism whereby loss of function NOD2 mutations confers risk, namely through altered differentiation of blood monocytes. It sharpens current research efforts involved in serial tissue and blood analyses to define how non-response or loss-of-response to anti-TNF therapies may be rescued.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: A deeper understanding of major genetic and cellular factors that drive Crohn’s disease will be required to substantially improve outcomes, over time. We define a new therapeutic target which may be tested in future studies; these studies may help tailor treatments more effectively for individual patients with Crohn’s disease. To further understand disease pathogenesis and refine treatment timing, it will be important to continue using novel single-cell technology platforms combined with prospective human studies.

No disclosures

Citation:

Nayar S, Morrison JK, Giri M, et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn’s disease. Nature. 2021 Mar. DOI: 10.1038/s41586-021-03484-5.

May 3, 2021 @ 6:51 pm

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