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Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mut...

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Autores principales: Venturini, Arianna, Borrelli, Anna, Musante, Ilaria, Scudieri, Paolo, Capurro, Valeria, Renda, Mario, Pedemonte, Nicoletta, Galietta, Luis J. V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584557/
https://www.ncbi.nlm.nih.gov/pubmed/34769402
http://dx.doi.org/10.3390/ijms222111972
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author Venturini, Arianna
Borrelli, Anna
Musante, Ilaria
Scudieri, Paolo
Capurro, Valeria
Renda, Mario
Pedemonte, Nicoletta
Galietta, Luis J. V.
author_facet Venturini, Arianna
Borrelli, Anna
Musante, Ilaria
Scudieri, Paolo
Capurro, Valeria
Renda, Mario
Pedemonte, Nicoletta
Galietta, Luis J. V.
author_sort Venturini, Arianna
collection PubMed
description Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation.
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spelling pubmed-85845572021-11-12 Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene Venturini, Arianna Borrelli, Anna Musante, Ilaria Scudieri, Paolo Capurro, Valeria Renda, Mario Pedemonte, Nicoletta Galietta, Luis J. V. Int J Mol Sci Article Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation. MDPI 2021-11-04 /pmc/articles/PMC8584557/ /pubmed/34769402 http://dx.doi.org/10.3390/ijms222111972 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Venturini, Arianna
Borrelli, Anna
Musante, Ilaria
Scudieri, Paolo
Capurro, Valeria
Renda, Mario
Pedemonte, Nicoletta
Galietta, Luis J. V.
Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title_full Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title_fullStr Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title_full_unstemmed Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title_short Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
title_sort comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the cftr gene
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584557/
https://www.ncbi.nlm.nih.gov/pubmed/34769402
http://dx.doi.org/10.3390/ijms222111972
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