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Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense

Daniel R McHugh1, Calvin U Cotton2,3, Craig A Hodges1,2

  • 1Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA.

International Journal of Molecular Sciences
|January 5, 2021
PubMed

Insights

Combining nonsense-mediated decay (NMD) inhibitors with readthrough agents shows promise for treating genetic disorders caused by premature termination codons (PTCs). This synergistic approach can restore functional protein levels, offering a new therapeutic avenue.

Area of Science:

  • Genetics
  • Molecular Biology
  • Pharmacology

Background:

  • Heritable genetic disorders often stem from nonsense mutations, creating premature termination codons (PTCs).
  • PTCs disrupt protein synthesis and trigger mRNA degradation via nonsense-mediated decay (NMD).
  • Current therapies aim to bypass PTCs through ribosomal readthrough or inhibit NMD.

Purpose of the Study:

  • To investigate the synergistic efficacy of combining NMD inhibitors with various readthrough agents.
  • To assess the restoration of functional CFTR protein in a mouse model with a G542X nonsense mutation.

Main Methods:

  • Functional analysis of CFTR protein in primary cells from a G542X mutant mouse model.
  • Testing combinations of known NMD inhibitors (SMG1i) with multiple readthrough agents (G418, gentamicin, paromomycin, amikacin, tobramycin, PTC124, escin, amlexanox).

Main Results:

  • Synergistic effects were observed between SMG1i and readthrough agents G418, gentamicin, and paromomycin.
  • No synergy was found with amikacin, tobramycin, PTC124, escin, or amlexanox.
  • NMD inhibition enhanced functional protein restoration following ribosomal readthrough.

Conclusions:

  • Combining NMD inhibitors with specific readthrough agents can increase functional protein quantity.
  • This combination therapy represents a potential strategy for treating genetic disorders caused by nonsense mutations.
Keywords:
aminoglycosidecystic fibrosisintestinal organoidnonsense-mediated decayorganoidpremature termination codonreadthrough

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