Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
Journal
EMBO Molecular Medicine
ISSN
1757-4684
Date Issued
2024
Author(s)
Grace Tartaglia
Neil Patel
Abigail Varughese
Lauren E Israel
Pyung Hun Park
Michael H Alexander
Shiv Poojan
Qingqing Cao
Brenda Solomon
Zachary M Padron
Jonathan A Dyer
Jemima E Mellerio
John A McGrath
Julio Salas-Alanis
Lin Han
Andrew P South
Type
journal-article
Abstract
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
Cite this document
Tartaglia, G., Fuentes, I., Patel, N., Varughese, A., Israel, L. E., Park, P. H., Alexander, M. H., Poojan, S., Cao, Q., Solomon, B., Padron, Z. M., Dyer, J. A., Mellerio, J. E., McGrath, J. A., Palisson, F., Salas-Alanis, J., Han, L., & South, A. P. (2024). Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa. EMBO Molecular Medicine, 16(4), 870-884. https://doi.org/10.1038/s44321-024-00048-8