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Updated: Jun 5, 2025

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Exploring the therapeutic potential of modulating nonsense-mediated mRNA decay

Mary McMahon1, Lynne E Maquat2,3

  • 1ReviR Therapeutics, Brisbane, California 94005, USA mary.mcmahon@revirtx.com lynne_maquat@urmc.rochester.edu.

RNA (New York, N.Y.)
|December 12, 2024
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) regulates gene expression and causes disease. Novel therapeutics aim to modulate NMD for treating genetic disorders, offering hope for new treatments.

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial cellular surveillance pathway involved in gene expression regulation.
  • NMD dysfunction is implicated in the pathogenesis of various genetic diseases.
  • Current therapeutic strategies explore modulating NMD for disease treatment.

Purpose of the Study:

  • To review emerging therapeutic approaches targeting the NMD pathway.
  • To discuss the potential of NMD modulation for treating genetic disorders.
  • To highlight challenges in the clinical development of NMD-targeting therapeutics.

Main Methods:

  • Review of current literature on NMD and therapeutic strategies.
  • Analysis of novel approaches for NMD modulation.
  • Discussion of clinical development challenges.

Main Results:

  • Several novel therapeutic strategies aim to directly counteract disease-causing mutations or globally dampen NMD activity.
  • Therapeutics can hijack or inhibit NMD machinery to modulate gene expression.
  • Pre-mRNA splicing modulation is explored to control transcript-specific NMD.

Conclusions:

  • Targeted and global NMD modulators (inhibitors and activators) show promise for revolutionizing genetic disorder treatment.
  • NMD-targeted therapies offer potential for diseases with high unmet medical needs.
  • Further research and clinical development are needed to overcome challenges in NMD-based therapeutics.
Keywords:
NMDgene therapypre-mRNA splicingsite-directed RNA editingsmall-molecule modulators of splicingsmall-molecule modulators of translation termination

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