A ML-framework for the discovery of next-generation IBD targets using a harmonized single-cell atlas of patient tissue

Abstract Target discovery for IBD has traditionally relied on genetic associations, which lack the cellular resolution needed to identify novel, actionable, cell type-specific disease pathways. Here, we describe an integrated analytical and experimental framework that leverages harmonized single-cell data to systematically discover novel therapeutic strategies for IBD. We used AMICA DB TM , Immunai’s harmonized database of single-cell RNA datasets to construct a harmonized 1 million single-cell atlas of the human intestine. We applied a machine learning framework (Immune Patient Representation, IPR) to identify disease-associated transcriptional programs and cell type-specific gene targets. Candidate targets were prioritized using atlas-derived metrics, refined using custom criteria emphasizing translational actionability, and validated across independent clinical cohorts. Select candidates were evaluated in human primary-cell models reflecting the target’s cell-type context. The IPR framework identified 85 disease-associated transcriptional programs and ranked 400 cell type-specific target genes across immune and stromal lineages. Disease-associated programs were interpreted using a structured AI-assisted reasoning framework for structured biological reasoning, linking them to IBD-relevant pathways and guiding the identification of novel, promising gene targets. Functional validation of two cell-type-specific candidates, PTGIR in myeloid cells and IL6ST in fibroblasts, confirmed the reduction of inflammatory and fibrotic pathways linked to IBD pathology. Multi-omic profiling and projection of in vitro phenotypes to patient datasets demonstrated the reversal of disease-associated programs via mechanisms distinct from those of existing biologics. Our single-cell anchored, machine-learning framework integrates in silico discovery with experimental validation, revealing new cell type-specific therapeutic opportunities and supporting a scalable approach for precision target discovery in IBD and other immune-mediated diseases.