Photo Credit: Miriam Doerr

This study investigates the pro-fibrotic role of the Notch pathway in Recessive Dystrophic Epidermolysis Bullosa (RDEB), revealing elevated JAG1 and NOTCH1 levels in RDEB fibroblasts and proposing γ-secretase inhibitors DAPT and PF-03084014 as potential therapeutic strategies for mitigating RDEB-associated fibrosis.

The following is a summary of “Gamma-secretase inhibitors down-regulate the pro-fibrotic Notch signaling pathway in recessive dystrophic epidermolysis bullosa,” published in the January 2024 issue of Dermatology by Condorelli et al.

Recessive dystrophic epidermolysis bullosa (RDEB) is an uncommon skin fragility disorder resulting from mutations in COL7A1, characterized by persistent blistering triggered by trauma, chronic wounds with inflammation, and progressive fibrosis, leading to severe complications. Currently lacking a cure for RDEB-associated fibrosis, their investigation delves into the pro-fibrotic role of the Notch pathway, identified in previous studies and supported by emerging evidence in various skin disorders, including RDEB. This research aims to elucidate the involvement of Notch signaling in RDEB pathogenesis and assess the impact of its inhibition using γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). 

Their analyses reveal up-regulation of JAG1 and cleaved NOTCH1 in primary RDEB fibroblasts (RDEB-FBs) compared to controls, with elevated protein levels upon TGF-β1 stimulation. Functional assays uncover the participation of the JAG1/NOTCH1 axis in RDEB fibrosis, highlighting the efficacy of its blockade in mitigating various fibrotic traits. Specifically, RDEB-FBs treated with PF-03084014 exhibit a substantial reduction in contractility, decreased secretion of TGF-β1 and collagens, and down-regulation of several fibrotic proteins. While the reduction of fibrotic traits is less pronounced in DAPT-treated cells than those treated with PF-03084014, their study presents novel therapeutic strategies to counteract the onset and progression of RDEB fibrosis. These findings contribute valuable insights into potential treatments for RDEB-associated fibrosis, emphasizing the promising role of Notch pathway inhibition as a targeted therapeutic approach for this challenging disorder.

Source: sciencedirect.com/science/article/abs/pii/S0022202X24000010