A Therapeutic Strategy for Atopic Dermatitis by Targeting the WNT Pathway

Background

Limited options exist for the effective treatment of Atopic dermatitis (AD), a common inflammatory condition affecting 20% of infants and children, due to a lack of understanding of specific treatment targets for AD. An improved genomic understanding of AD is needed to identify specific genetic targets and cell signaling pathways that contribute to the inflammatory responses in AD in order to design and develop therapies with a sound mechanism of action.

Recent reports suggest that Wnt-dependent signaling pathways play critical roles in skin development and maintenance by providing extrinsic cellular cues and regulating cellular pathways. However, the exact role of WNT pathways in causing AD is still unclear and warrants greater investigation to determine their potential for therapeutic use.

Technology Overview

This invention used a genome-wide CRISPR-Cas9 screen in human HEK293T cells in the ma mouse model, with a knockout of the TMEM79 gene, to identify how TMEM79 acts as a potent inhibitor of the WNT/β-catenin signaling pathway possibly through negative regulation of WNT receptors. Thus, the current invention supports the notion that TMEM79/MATT is a predisposing gene for AD and that the deregulation of the WNT/β-catenin pathway, due to its importance in the formation and maintenance of the skin barrier, plays a role in AD and other chronic inflammatory skin diseases. Additionally, the investigators found that the elevated WNT signaling caused by knockout of HEK293T cells in the ma mouse model, can be suppressed by a small molecule that specifically inhibits WNT secretion. While the small molecule in question is being used in phase I clinical trials for cancer treatments, it can potentially be repurposed for use in AD treatments. 

Benefits

• TMEM79/MATT gene provides support for downregulation of the WNT signaling pathway and can act as a more viable target for measurement for AD and other chronic inflammatory skin conditions where the exact etiology is unknown.

Applications

• TMEM79 gene can be used for early detection and measurement of treatment efficacy of AD and other chronic inflammatory skin conditions via genome-wide CRISPR-Cas9 screens in both human/animal models
• The ma model can be used for R & D of AD and other chronic inflammatory skin conditions.
• TMEM79/MATT gene can be used for small molecule drug discovery for a primary or supplementary therapeutic agent for AD and other chronic inflammatory skin conditions (in vivo and in vitro).
• Application for repurposing current phase I small molecule anti-cancer treatments for AD

Publications:

Chen, M., Amado, N., Tan, J., Reis, A., Ge, M., Abreu, J. G., & He, X. (2020). TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis. Elife, 9, e56793