Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons

ERJ Open Research
Iwona PrankeAlexandre Hinzpeter

Abstract

Premature termination codons (PTCs) are generally associated with severe forms of genetic diseases. Readthrough of in-frame PTCs using small molecules is a promising therapeutic approach. Nonetheless, the outcome of preclinical studies has been low and variable. Treatment efficacy depends on: 1) the level of drug-induced readthrough, 2) the amount of target transcripts, and 3) the activity of the recoded protein. The aim of the present study was to identify, in the cystic fibrosis transmembrane conductance regulator (CFTR) model, recoded channels from readthrough therapy that may be enhanced using CFTR modulators. First, drug-induced readthrough of 15 PTCs was measured using a dual reporter system under basal conditions and in response to gentamicin and negamycin. Secondly, exon skipping associated with these PTCs was evaluated with a minigene system. Finally, incorporated amino acids were identified by mass spectrometry and the function of the predicted recoded CFTR channels corresponding to these 15 PTCs was measured. Nonfunctional channels were subjected to CFTR-directed ivacaftor-lumacaftor treatments. The results demonstrated that CFTR modulators increased activity of recoded channels, which could also be confirmed in cell...Continue Reading

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Citations

Jan 23, 2020·American Journal of Primatology·Jennifer L Taylor-CousarNeeraj Sharma
Jul 8, 2020·International Journal of Molecular Sciences·Valentino BezzerriMarco Cipolli
Mar 16, 2019·Frontiers in Pharmacology·Iwona PrankeIsabelle Sermet-Gaudelus
Nov 28, 2018·Molecular Diagnosis & Therapy·Giulio Cabrini
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Nov 11, 2018·Molecular Diagnosis & Therapy·Valentino Bezzerri, Marco Cipolli
Jan 12, 2021·Expert Opinion on Drug Delivery·Douweh Leyla Gbian, Abdelwahab Omri
Dec 17, 2020·International Journal of Molecular Sciences·Silvia LombardiAlessio Branchini
Mar 23, 2021·Cellular and Molecular Life Sciences : CMLS·Patrícia Martins-Dias, Luísa Romão
Feb 23, 2021·American Journal of Respiratory Cell and Molecular Biology·Venkateshwar MutyamSteven M Rowe
Dec 21, 2020·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Natacha MartinAlexandre Hinzpeter
Jul 31, 2021·Journal of Experimental Pharmacology·Madalena C PintoMiquéias Lopes-Pacheco

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Clinical Trials Mentioned

NCT02965326

Software Mentioned

R
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