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

D D Zomer-van Ommen; L A W Vijftigschild; E Kruisselbrink; A M Vonk; J F Dekkers; H M Janssens; K M de Winter-de Groot; C K van der Ent; J M Beekman

doi:10.1016/j.jcf.2015.07.007

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.

Authors

D D Zomer-van Ommen¹, L A W Vijftigschild¹, E Kruisselbrink¹, A M Vonk¹, J F Dekkers¹, H M Janssens², K M de Winter-de Groot³, C K van der Ent³, J M Beekman⁴

Affiliations

¹ Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
² Dept of Pediatrics, Sophia Children's Hospital/Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
³ Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands.
⁴ Laboratory of Translational Immunology, UMC Utrecht, The Netherlands; Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands. Electronic address: J.Beekman@umcutrecht.nl.

PMID: 26255232
DOI: 10.1016/j.jcf.2015.07.007

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