Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa

  • EMBO Mol Med. 2024 Mar 10. doi: 10.1038/s44321-024-00048-8.
Grace Tartaglia  1 ,  Ignacia Fuentes  2  3  4 ,  Neil Patel  5 ,  Abigail Varughese  1 ,  Lauren E Israel  1 ,  Pyung Hun Park  1 ,  Michael H Alexander  1 ,  Shiv Poojan  1 ,  Qingqing Cao  1 ,  Brenda Solomon  1 ,  Zachary M Padron  1 ,  Jonathan A Dyer  6 ,  Jemima E Mellerio  7 ,  John A McGrath  7 ,  Francis Palisson  2  8 ,  Julio Salas-Alanis  9 ,  Lin Han  5 ,  Andrew P South  10  11  12  13
Affiliations
  • 1. Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 2. DEBRA Chile, Santiago, Chile.
  • 3. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • 4. Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Universidad de Desarrollo, Santiago, Chile.
  • 5. School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
  • 6. Department of Dermatology, University of Missouri School of Medicine, Columbia, MO, USA.
  • 7. St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
  • 8. Servicio de Dermatologia, Facultad de Medicina Clínica Alemana-Universidad de Desarrollo, Santiago, Chile.
  • 9. Instituto Dermtaologico de Jalisco, Guadalajara, Mexico.
  • 10. Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA. [email protected].
  • 11. The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Thomas Jefferson University, Philadelphia, PA, USA. [email protected].
  • 12. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. [email protected].
  • 13. Department of Otolaryngology Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, USA. [email protected].
PMID: 38462666 DOI: 10.1038/s44321-024-00048-8
Abstract

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.

Keywords
Antivirals; Collagen; Drug Repurposing; Fibrosis; Recessive Dystrophic Epidermolysis Bullosa.
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