InsideOut Bio

Every approved atopic dermatitis (AD) drug blocks the type-2 pathway from the outside: injectable antibodies against extracellular cytokines. The frontier is inside the cell, at the transcription factors that run the allergic program, because degrading a master node promises deeper, oral suppression. STAT6 is the proof of concept, but no one had systematically asked which other intracellular regulators would collapse the program if shut down. I screened a genome-scale CD4⁺ T-cell Perturb-seq atlas (~34,000 knockout signatures), scoring every perturbation for how strongly it phenocopies the STAT6 and GATA3 "Th2-collapse" signature. The pipeline recovers both anchors at rank 1 which is a built-in positive control and surfaced an unexpected finding: in circulating cells, STAT6 and GATA3 knockouts anti-correlate, meaning GATA3 maintains the type-2 program STAT6-independently. This is corroborated three ways (cosine screen, an independent supervised classifier that ranks GATA3 #4/6,923 but STAT6 #4,809, and prior literature(Ouyang 2000, Yamashita 2004), and it reproduces in independent lesional-skin scRNA-seq (GSE147424). I then expanded to every AD immune axis a T cell can represent (JAK-STAT, Th22/AHR, Th1, activation-tone, AD-GWAS TFs), cross-referenced the known AD drug universe, and layered on degrader-tractability, human-genetics (allergic-disease GWAS), and literature-novelty annotation. Deliverables: a druggability-annotated multi-axis target map, a reusable Th2-collapse classifier, and a fully rerunnable pipeline others can build on. Why it matters: it converts a single validated drug target (STAT6) into a ranked, evidence-annotated landscape of the next ones with IL4R, ORAI1, SMARCA4, SMAD4 and a TYK2-axis lead (IFNAR1/anifrolumab) surfacing as candidates, and it delivers a classifier that scores any new perturbation for Th2-collapse potential.

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