2. Academic Validation
  3. Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa

Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa

  • Sci Rep. 2024 Aug 16;14(1):18969. doi: 10.1038/s41598-024-67398-8.
Irene Jover 1,  Maria C Ramos 2,  María José Escámez 3 4 5 6,  Estrella Lozoya 1,  José R Tormo 2,  Diana de Prado-Verdún 6,  Ángeles Mencía 3 4 5 6,  Mercè Pont 1,  Carles Puig 1,  Marie-Helene Larraufie 1,  Cristina Gutiérrez-Caballero 1,  Fernando Reyes 2,  Juan Luis Trincado 1,  Vicente García-González 1,  Rosario Cerrato 1,  Miriam Andrés 1,  Maribel Crespo 1,  Francisca Vicente 2,  Nuria Godessart 1,  Olga Genilloud 2,  Fernando Larcher 7 8 9 10,  Arsenio Nueda 11
Affiliations

Affiliations

  • 1 R&D Centre, Almirall S.A., Laureà Miró 408-410, 08980, Sant Feliu de Llobregat, Barcelona, Spain.
  • 2 Fundación MEDINA, Parque Tecnológico de La Salud, Av. Conocimiento 34, 18016, Granada, Spain.
  • 3 Departamento de Bioingeniería E Ingeniería Aeroespacial (UC3M), División de Biomedicina Epitelial, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidad Carlos III de Madrid (UC3M), Madrid, Spain.
  • 4 Unidad de Innovación Biomédica. Centro de Investigaciones Energéticas, U714-CIBER de Enfermedades Raras (CIBERER-ISCIII), Madrid, Spain.
  • 5 Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (IISFJD), Madrid, Spain.
  • 6 Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
  • 7 Departamento de Bioingeniería E Ingeniería Aeroespacial (UC3M), División de Biomedicina Epitelial, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. fernando.larcher@ciemat.es.
  • 8 Unidad de Innovación Biomédica. Centro de Investigaciones Energéticas, U714-CIBER de Enfermedades Raras (CIBERER-ISCIII), Madrid, Spain. fernando.larcher@ciemat.es.
  • 9 Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (IISFJD), Madrid, Spain. fernando.larcher@ciemat.es.
  • 10 Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. fernando.larcher@ciemat.es.
  • 11 R&D Centre, Almirall S.A., Laureà Miró 408-410, 08980, Sant Feliu de Llobregat, Barcelona, Spain. arsenio.nueda@almirall.com.
PMID: 39152155 DOI: 10.1038/s41598-024-67398-8
Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin Cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age. A frequent class of mutations in RDEB is premature termination codons (PTC), which appear in homozygosity or compound heterozygosity with other mutations. RDEB has no cure and current therapies are mostly palliative. Using patient-derived keratinocytes and a library of 8273 small molecules and 20,160 microbial extracts evaluated in a phenotypic screening interrogating C7 levels, we identified three active chemical series. Two of these series had PTC readthrough activity, and one upregulated C7 mRNA, showing synergistic activity when combined with the reference readthrough molecule gentamicin. These compounds represent novel potential small molecule-based systemic strategies that could complement topical-based treatments for RDEB.

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