Dupilumab normalizes the eosinophilic esophagitis disease transcriptome

Area of Science:

• Molecular biology and immunology of esophageal diseases.
• Transcriptomics and gene expression analysis in inflammatory conditions.
• Pharmacology of targeted biologic therapies.

Background:

• Eosinophilic esophagitis (EoE) is a type 2 inflammatory disease (T2ID) of the esophagus.
• EoE is characterized by eosinophilic inflammation and an altered esophageal transcriptome.
• Dupilumab, a monoclonal antibody blocking IL-4 and IL-13, is approved for EoE and other T2IDs.

Purpose of the Study:

• To investigate the effect of dupilumab on the dysregulated esophageal transcriptome in EoE.
• To analyze transcriptome changes in pediatric, adolescent, and adult EoE patients treated with dupilumab.

Main Methods:

• Analysis of esophageal biopsies from EoE patients before and after dupilumab treatment.
• Utilized data from three placebo-controlled clinical trials involving dupilumab.
• Transcriptome changes were assessed across pediatric, adolescent, and adult patient groups.

Main Results:

• Dupilumab treatment normalized the EoE disease transcriptome, including gene signatures for eosinophils, mast cells, and fibrosis.
• Gene ontology analysis revealed normalization of 41 biologic processes, some independent of eosinophils.
• Transcriptome changes were comparable and sustained through week 52 in all age groups.

Conclusions:

• Interleukin-4 (IL-4) and IL-13 are key drivers of molecular differences in EoE esophageal mucosa.
• Dupilumab's clinical benefit in EoE is consistent with its effect on IL-4/IL-13 signaling.
• The study supports IL-4/IL-13 as critical targets for EoE treatment.