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

J Cyst Fibros. 2016 Mar;15(2):158-62. doi: 10.1016/j.jcf.2015.07.007. Epub 2015 Aug 5.

Abstract

Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.

Keywords: Cystic fibrosis; G418; Intestinal organoids; Nonsense suppression; PTC124; Read-through.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Coccidiostats / therapeutic use
  • Codon, Nonsense / drug effects*
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Gentamicins / therapeutic use*
  • Humans
  • Organoids / cytology*
  • Oxadiazoles / therapeutic use*
  • RNA / genetics

Substances

  • Coccidiostats
  • Codon, Nonsense
  • Gentamicins
  • Oxadiazoles
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • RNA
  • antibiotic G 418
  • ataluren