Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa

• Published in: EMBO molecular medicine Vol. 16; no. 4; pp. 870 - 884
• Main Authors: Tartaglia, Grace, Fuentes, Ignacia, Patel, Neil, Varughese, Abigail, Israel, Lauren E, Park, Pyung Hun, Alexander, Michael H, Poojan, Shiv, Cao, Qingqing, Solomon, Brenda, Padron, Zachary M, Dyer, Jonathan A, Mellerio, Jemima E, McGrath, John A, Palisson, Francis, Salas-Alanis, Julio, Han, Lin, South, Andrew P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2024; Springer Nature
• Subjects: Antivirals; Biomedical and Life Sciences; Biomedicine; Collagen; Drug Repurposing; EMBO08; EMBO38; Fibrosis; Molecular Medicine; Recessive Dystrophic Epidermolysis Bullosa; Recessive Dystrophic Epidermolysis Bullosa; Drug Repurposing; Collagen; Fibrosis; Antivirals
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00048-8

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases. Synopsis The antiviral daclatasvir was identified as an anti-fibrotic compound in a high throughput screen using a novel in vitro model of fibrosis. Daclatasvir improved life quality and survival in a mouse model of recessive dystrophic epidermolysis bullosa (RDEB). Endogenously-produced matrix from primary patient fibroblasts can be utilized as a detachment assay to screen compounds for anti-fibrotic repurposing. Antivirals are a novel class of fibrosis preventatives in RDEB as verified from two library screens. Daclatasvir was our repurposed hit of interest for preventing fibrosis in RDEB. Daclatasvir downregulated the TGFβ signaling pathway targets. Daclatasvir improved the life quality of RDEB mice. The antiviral daclatasvir was identified as an anti-fibrotic compound in a high throughput screen using a novel in vitro model of fibrosis. Daclatasvir improved life quality and survival in a mouse model of recessive dystrophic epidermolysis bullosa (RDEB).