Activation of Aryl Hydrocarbon Receptor (AHR) as a therapeutic for Eosinophilic Esophagitis (EoE).
Recent studies have linked the importance of AHR as a regulator of EoE pathogenesis and the potential of AHR activation by small molecules as EoE therapy.
Currently, there are no US FDA-approved small molecule treatments for EoE. Available off-label standard of care treatments, including proton pump inhibitors and corticosteroids, do not show a response in up to half of EoE patients. SPINK7 is an epithelial serine protease inhibitor that is highly expressed in the esophagus and markedly decreased in patients with eosinophilic esophagitis (EoE). Loss of SPINK7 in esophageal epithelial cells promotes barrier impairment and pro-inflammatory innate immune responses. Activation of AHR by delivery of AHR ligands increase the expression of SPINK7 as well as epithelial barrier and differentiation genes that are important for inducing the barrier function and preventing inflammatory pathways. Blocking AHR with an AHR antagonist, inhibited AHR-ligand dependent SPINK7 expression. Activation of AHR induces a transcription program, including SPINK7 expression, and has been shown to be a novel therapeutic target for small molecule treatment of EoE.
- Improved barrier function in EoE
- Blocks epithelial immune response
- Novel small molecule therapeutic treatment of EoE
Estimated occurrences of EoE in pediatric and adult populations are 43–57 per 100,000 persons. More effective or curative treatments for EoE are a critical unmet need and the current US market is valued around $156 million with an expected growth to $1.9 Billion by 2030.
Nurit Azouz, PhD & Marc Rothenberg, MD, PhD, Division of Allergy & Immunology