Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa

Angelo Giuseppe Condorelli; Rebecca Nobili; Anita Muglia; Giorgia Scarpelli; Elisa Marzuolo; Cristiano De Stefanis; Rossella Rota; Andrea Diociaiuti; Rita Alaggio; Daniele Castiglia; Teresa Odorisio; May El Hachem; Giovanna Zambruno

doi:10.1016/j.jid.2023.10.045

Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa

J Invest Dermatol. 2024 Jan 17:S0022-202X(24)00001-0. doi: 10.1016/j.jid.2023.10.045. Online ahead of print.

Affiliations

¹ Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: agiuseppe.condorelli@opbg.net.
² Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
³ Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴ Department of Hematology and Oncology, Cell and Gene Therapy Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁵ Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁶ Pathology Unit and Predictive Molecular Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "La Sapienza", Rome, Italy.
⁷ Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

PMID: 38237731
DOI: 10.1016/j.jid.2023.10.045

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-β1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-β1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

Keywords: DAPT; Fibroblasts; JAG1; Nirogacestat (PF-03084014); skin fibrosis.