Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
EMBO molecular medicine - 16(2024), 4 vom: 10. Apr., Seite 870-884 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tartaglia, Grace [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s44321-024-00048-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369523946 |
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| 245 | 1 | 0 | |a Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Collagen | |
| 650 | 4 | |a Drug Repurposing | |
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| 650 | 7 | |a Pyrrolidines |2 NLM | |
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| 700 | 1 | |a Fuentes, Ignacia |e verfasserin |4 aut | |
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| 700 | 1 | |a Varughese, Abigail |e verfasserin |4 aut | |
| 700 | 1 | |a Israel, Lauren E |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Pyung Hun |e verfasserin |4 aut | |
| 700 | 1 | |a Alexander, Michael H |e verfasserin |4 aut | |
| 700 | 1 | |a Poojan, Shiv |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Qingqing |e verfasserin |4 aut | |
| 700 | 1 | |a Solomon, Brenda |e verfasserin |4 aut | |
| 700 | 1 | |a Padron, Zachary M |e verfasserin |4 aut | |
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| 700 | 1 | |a Palisson, Francis |e verfasserin |4 aut | |
| 700 | 1 | |a Salas-Alanis, Julio |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a South, Andrew P |e verfasserin |4 aut | |
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