Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa

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dc.contributor.authorTartaglia, Grace
dc.contributor.authorFuentes, Ignacia
dc.contributor.authorPatel, Neil
dc.contributor.authorVarughese, Abigail
dc.contributor.authorIsrael, Lauren E.
dc.contributor.authorPark, Pyung Hun
dc.contributor.authorAlexander, Michael H.
dc.contributor.authorPoojan, Shiv
dc.contributor.authorCao, Qingqing
dc.contributor.authorSolomon, Brenda
dc.contributor.authorPadron, Zachary M.
dc.contributor.authorDyer, Jonathan A.
dc.contributor.authorMellerio, Jemima E.
dc.contributor.authorMcGrath, John A.
dc.contributor.authorPalisson, Francis
dc.contributor.authorSalas-Alanis, Julio
dc.contributor.authorHan, Lin
dc.contributor.authorSouth, Andrew P.
dc.date.accessioned2025-01-20T16:17:52Z
dc.date.available2025-01-20T16:17:52Z
dc.date.issued2024
dc.description.abstractRecessive 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 TGF beta 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.
dc.description.abstractThe 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 TGF beta signaling pathway targets. Daclatasvir improved the life quality of RDEB mice.
dc.description.abstractThe 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).
dc.fuente.origenWOS
dc.identifier.doi10.1038/s44321-024-00048-8
dc.identifier.eissn1757-4684
dc.identifier.issn1757-4676
dc.identifier.urihttps://doi.org/10.1038/s44321-024-00048-8
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/90619
dc.identifier.wosidWOS:001222081700017
dc.issue.numero4
dc.language.isoen
dc.pagina.final884
dc.pagina.inicio870
dc.revistaEmbo molecular medicine
dc.rightsacceso restringido
dc.subjectFibrosis
dc.subjectCollagen
dc.subjectRecessive Dystrophic Epidermolysis Bullosa
dc.subjectDrug Repurposing
dc.subjectAntivirals
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleAntiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
dc.typeartículo
dc.volumen16
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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