Browsing by Author "Solomon, Brenda"

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    Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
    (2024) 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.
    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 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.