Defective STAT3 signaling: Linking molecular pathways in VEOIBD patients to precision-based IBD therapeutic approaches targeting IL12/23

About This Grant

PROJECT SUMMARY/ABSTRACT Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset at age <6 years and is associated with a more severe and aggressive disease course. Up to 10% of affected children have an underlying disease-causing monogenic immunodeficiency, such as defects in IL10 signaling, but the mechanisms driving disease in the majority of patients remain unknown. Furthermore, there are no biologic or small molecule therapies FDA-approved for use in IBD in this age group and current treatment approaches rely on empiric trials of medications approved for adult IBD. Collectively, these factors contribute to significant treatment challenges in VEOIBD and to substantial cost and morbidity stemming from delays in remission, growth failure, steroid- dependence, hospitalization, and surgical intervention. There is an urgent need to define disease mechanisms that enable biomarker-guided treatment selection in both VEOIBD and IBD more broadly. We have identified a unique subgroup of VEOIBD patients defined by markedly diminished activation of STAT3 in response to multiple cytokines, including IL10 (“STAT3-aberrant” or STAT3-abr, n=7). These patients share a clinical phenotype characterized by severe, refractory colonic disease without an identifiable monogenic basis and a blood transcriptional signature characterized by increased IL23 signaling. Notably, four of these patients have been treated with anti-IL12/23 or anti-IL23 following multiple prior medication failures, and all four achieved rapid, sustained remission, implicating IL23 as a key disease driver and therapeutic target. The overall goals of this proposal are to define the mechanisms underlying this STAT3-abr signaling state and to leverage signatures of this state as biomarker(s) of response to IL23-blocking therapies. Our central hypothesis is that excessive IL23 signaling promotes preferential activation of pro-inflammatory (e.g., IL23) STAT3-dependent programs at the expense of anti-inflammatory (e.g., IL10) STAT3-dependent programs in this STAT3-abr group and a subset of patients with later-onset disease. Aim 1 will define STAT3-dependent signaling and how IL23 modulates that signaling in STAT3-abr patients compared to controls. Aim 2 will examine epigenomic and transcriptional consequences of the STAT3-abr signaling state by examining differences in chromatin accessibility, STAT3-DNA binding, cellular composition, and gene expression in STAT3-abr patients compared to controls. Aim 3 will develop and evaluate a multimodal predictive tool that incorporates STAT3-abr clinical and transcriptional features to predict response to IL23-blocking therapy in pediatric and adult IBD cohorts. Completion of this work will mechanistically define a novel STAT3 signaling state in VEOIBD and develop a biomarker predictive of response to IL23-blocking therapies, impacting personalized medicine opportunities for IBD patients of all ages.