Strategy for the optimization of read-through therapy for junctional epidermolysis bullosa with COL17A1 nonsense mutation

Abstract: Read-through therapy suppresses premature termination codons and induces read-through activity, consequently restoring missing proteins. Aminoglycosides are widely studied as read-through drugs in different human genetic disorders, including hereditary skin diseases. Our previous work revealed that aminoglycosides affect COL17A1 nonsense mutations and represent a therapeutic option to alleviate disease severity. However, the amount of restored type XVII collagen (C17) in C17-deficient junctional epidermolysis bullosa keratinocytes was <1% relative to that in normal keratinocytes and was achieved only after high-dose gentamicin treatment, which induced deep transcriptional changes. Therefore, in this study, we designed a strategy combining aminoglycosides with compounds known to reduce their side effects. We developed translational read-through–inducing drug cocktail, version 5 containing low dosage of aminoglycosides, CC-90009, NMDI-14, melatonin, and apocynin that was able to induce about 20% of missing C17 without cell toxicity or an effect on in vitro wound closure. Translational read-through–inducing drugs cocktail, version 5 significantly induced COL17A1 expression and reverted the proinflammatory phenotype of C17-deficient junctional epidermolysis bullosa keratinocytes. Evaluation of this drug cocktail regarding its stability, penetration, and efficacy as a topical treatment remains to be determined. Translational read-through–inducing drug cocktail, version 5 might represent an improved therapeutic strategy for junctional epidermolysis bullosa and for other genetic skin disorders

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: The journal of investigative dermatology. - 144, 10 (2024) , 2221-2229.e1, ISSN: 1523-1747

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2024
• Creator: Sayar, Saliha Beyza ; Has, Cristina

Further information

• DOI: 10.1016/j.jid.2024.02.027
• URN: urn:nbn:de:bsz:25-freidok-2490402
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:25 AM CEST