Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons

Autor: Isabelle Sermet-Gaudelus, Laure Bidou, Emmanuelle Girodon, Benoit Chevalier, Alexandre Hinzpeter, Iwona Pranke, Aurélie Hatton, Danielle Tondelier, Sabrina Karri, Natacha Martin, Matthieu Coupet, Pascale Fanen, Aleksander Edelman, Bruno Costes, David Cornu, Sandra Blanchet, Olivier Namy
Přispěvatelé: Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de physique des interfaces et des couches minces [Palaiseau] (LPICM), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Namy, Olivier
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Pulmonary and Respiratory Medicine
[SDV]Life Sciences [q-bio]
lcsh:Medicine
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Cystic fibrosis
03 medical and health sciences
Basal (phylogenetics)
Genotype
medicine
Author Correction
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
business.industry
lcsh:R
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Original Articles
medicine.disease
Exon skipping
Cystic fibrosis transmembrane conductance regulator
3. Good health
Amino acid
[SDV] Life Sciences [q-bio]
030104 developmental biology
chemistry
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Cancer research
biology.protein
business
Function (biology)
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Minigene
Zdroj: ERJ Open Research
ERJ Open Research, European Respiratory Society, 2018, 4 (1), pp.00080-2017. ⟨10.1183/23120541.00080-2017⟩
ERJ Open Research, Vol 4, Iss 1 (2018)
ERJ Open Research, 2018, 4 (1), pp.00080-2017. ⟨10.1183/23120541.00080-2017⟩
ISSN: 2312-0541
Popis: 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 cells derived from a patient. In conclusion, this work will provide a framework to adapt treatments to the patient's genotype by identifying the most efficient molecule for each PTC and the recoded channels needing co-therapies to rescue channel function.
This study identified readthrough-recoded CFTR channels, the activity of which could be enhanced using CFTR modulators http://ow.ly/f7Gd30hBCeG
Databáze: OpenAIRE
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