Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa.

Authors

Velina S. Atanasova, Thomas Jefferson UniversityFollow
Qiujie Jiang, Thomas Jefferson UniversityFollow
Marco Prisco, Thomas Jefferson UniversityFollow
Christina Gruber, Paracelsus Medical University
Josefina Piñón Hofbauer, Paracelsus Medical University
Mei Chen, University of Southern California, Los Angeles
Cristina Has, University of Freiburg
Leena Bruckner-Tuderman, University of Freiburg
John A. McGrath, King's College London
Jouni UittoFollow
Andrew P. South, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

9-1-2017

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Journal of Investigative Dermatology, Volume 137, Issue 9, September 2017, Pages 1842-1849.

The published version is available at https://doi.org/10.1016/j.jid.2017.05.011. Copyright © Atanasova et al.

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder caused by the lack of functional type VII collagen, leading to skin fragility and subsequent trauma-induced separation of the epidermis from the underlying dermis. A total of 46% of patients with RDEB harbor at least one premature termination codon (PTC) mutation in COL7A1, and previous studies have shown that aminoglycosides are able to overcome RDEB PTC mutations by inducing "read-through" and incorporation of an amino acid at the PTC site. However, aminoglycoside toxicity will likely prevent widespread clinical application. Here the FDA-approved drug amlexanox was tested for its ability to read-through PTC mutations in cells derived from patients with RDEB. Eight of 12 different PTC alleles responded to treatment and produced full length protein, in some cases more than 50% relative to normal controls. Read-through type VII collagen was readily detectable in cell culture media and also localized to the dermal-epidermal junction in organotypic skin culture. Amlexanox increased COL7A1 transcript and the phosphorylation of UPF-1, an RNA helicase associated with nonsense-mediated mRNA decay, suggesting that amlexanox inhibits nonsense-mediated mRNA decay in cells from patients with RDEB that respond to read-through treatment. This preclinical study demonstrates the potential of repurposing amlexanox for the treatment of patients with RDEB harboring PTC mutation in COL7A1.

Recommended Citation

Atanasova, Velina S.; Jiang, Qiujie; Prisco, Marco; Gruber, Christina; Hofbauer, Josefina Piñón; Chen, Mei; Has, Cristina; Bruckner-Tuderman, Leena; McGrath, John A.; Uitto, Jouni; and South, Andrew P., "Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa." (2017). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 99.
https://jdc.jefferson.edu/dcbfp/99

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

28549954

Language

English