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Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids

D D Zomer-van Ommen1, L A W Vijftigschild1, E Kruisselbrink1

  • 1Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.

Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
|August 10, 2015
PubMed

Insights

Premature termination codon read-through drugs show potential for cystic fibrosis treatment. However, current agents like PTC124 and G418 demonstrated limited efficacy in restoring CFTR function in patient-derived organoids.

Area of Science:

  • Genetics
  • Pharmacology
  • Rare Diseases

Background:

  • Premature termination codon (PTC) mutations are a significant cause of rare genetic diseases.
  • Read-through drugs offer a therapeutic strategy by enabling ribosomes to bypass PTCs, restoring protein function.
  • Cystic fibrosis (CF) is a prime target for PTC read-through therapies due to prevalent nonsense mutations.

Purpose of the Study:

  • To evaluate the efficacy of two read-through compounds, PTC124 and G418.
  • To assess their ability to restore cystic fibrosis transmembrane conductance regulator (CFTR) function in human intestinal organoids derived from CF patients with various PTC mutations.

Main Methods:

  • Utilized human intestinal organoids from CF patients with specific PTC mutations (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del, F508del/F508del).
  • Administered PTC124 and G418 to organoids to induce read-through of premature termination codons.
  • Assessed the functional restoration of CFTR protein and ion channel activity.

Main Results:

  • G418 treatment resulted in minimal restoration of CFTR function.
  • PTC124 did not show confirmed functional restoration of CFTR in the tested organoid models.
  • Significant variability in response was observed across different PTC mutation backgrounds.

Conclusions:

  • Current read-through drug candidates, including PTC124 and G418, exhibit limited efficacy for treating cystic fibrosis caused by nonsense mutations.
  • Development of more potent and effective read-through agents is crucial for successful therapeutic application in CF.
  • Patient-derived organoid models provide a valuable platform for assessing drug efficacy in personalized medicine approaches.
Keywords:
Cystic fibrosisG418Intestinal organoidsNonsense suppressionPTC124Read-through

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