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Rescue of nonsense mutations by amlexanox in human cells
Sara Gonzalez-Hilarion1, Terence Beghyn, Jieshuang Jia
1Université Lille Nord de France, IFR142, Lille, France.
Background:
Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough.
Methods:
Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs.
Results:
We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional.
Conclusions:
As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations.
Insights
Amlexanox, an existing drug, can restore full-length functional protein production from nonsense-mutated genes by blocking nonsense-mediated mRNA decay (NMD). This dual action offers a potential therapeutic strategy for genetic diseases and cancers caused by these mutations.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Nonsense mutations frequently cause genetic diseases and cancers.
- Nonsense-mediated mRNA decay (NMD) often prevents protein expression from mutated genes.
- Therapeutic strategies include NMD inhibition and nonsense mutation readthrough.
Purpose of the Study:
- To identify molecules that inhibit nonsense-mediated mRNA decay (NMD).
- To evaluate the effect of a selected molecule on nonsense-containing mRNA levels and protein synthesis in patient-derived cell lines.
Main Methods:
- A screening system was employed to identify NMD-blocking molecules.
- Three patient-derived cell lines with nonsense mutations were utilized.
- Assays measured nonsense-containing mRNA levels and full-length protein synthesis.
Main Results:
- Amlexanox, an established drug, was identified as an NMD inhibitor.
- Amlexanox increased nonsense-containing mRNA levels.
- Amlexanox efficiently induced the synthesis of functional full-length proteins from mutant mRNAs.
Conclusions:
- Amlexanox demonstrates dual activity: increasing mutant mRNA levels and enabling functional protein production.
- Amlexanox shows promise as a therapeutic agent for diseases stemming from nonsense mutations.
