Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa
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.
Authors
- Fernando Reyes (ORCID: https://orcid.org/0000-0003-1607-5106)
- Rosario Cerrato
- Fernando Larcher (ORCID: https://orcid.org/0000-0002-6771-3561)
- Arsenio Nueda (ORCID: https://orcid.org/0000-0001-8373-500X)
- Olga Genilloud (ORCID: https://orcid.org/0000-0002-4202-1219)
- Vicente García‐González (ORCID: https://orcid.org/0000-0003-3502-2237)
- Carles Puig
- María C. Ramos (ORCID: https://orcid.org/0000-0002-3674-615X)
- Mercè Pont
- Francisca Vicente
- Maria Jose Escamez (ORCID: https://orcid.org/0000-0002-5434-1885)
- José R. Tormo (ORCID: https://orcid.org/0000-0001-6984-2941)
- Juan L. Trincado (ORCID: https://orcid.org/0000-0001-5363-3774)
- Estrella Lozoya (ORCID: https://orcid.org/0000-0003-2422-2233)
- Cristina Gutiérrez‐Caballero
- Ángeles Mencía (ORCID: https://orcid.org/0000-0002-9977-9514)
- Núria Godessart (ORCID: https://orcid.org/0000-0003-3546-4924)
- María Gema Crespo
- Diana de Prado-Verdún (ORCID: https://orcid.org/0009-0005-1848-1732)
- Irene Jover
- Marie-Helene Larraufie
- Míriam Andrés
Institutions
- Instituto de Salud Carlos III (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Almirall (Spain) (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Fundación Medina (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Universidad Carlos III de Madrid (ES)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1038/s41598-024-67398-8
- Citations
- 3
- Primary Topic
- Skin and Cellular Biology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- King's College London
- European Commission
- Centro para el Desarrollo Tecnológico Industrial
- Almirall
- Instituto de Salud Carlos III