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 <i>CFTR</i> gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for othe...

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Autores principales:	Arianna Venturini, Anna Borrelli, Ilaria Musante, Paolo Scudieri, Valeria Capurro, Mario Renda, Nicoletta Pedemonte, Luis J. V. Galietta
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cystic fibrosis nonsense mutation chloride channel readthrough therapy CFTR rescue Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/90cee40555d5412c8ee9842eafddf790
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spelling	oai:doaj.org-article:90cee40555d5412c8ee9842eafddf7902021-11-11T17:23:37ZComprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene10.3390/ijms2221119721422-00671661-6596https://doaj.org/article/90cee40555d5412c8ee9842eafddf7902021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11972https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the <i>CFTR</i> 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.Arianna VenturiniAnna BorrelliIlaria MusantePaolo ScudieriValeria CapurroMario RendaNicoletta PedemonteLuis J. V. GaliettaMDPI AGarticlecystic fibrosisnonsense mutationchloride channelreadthrough therapyCFTR rescueBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11972, p 11972 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cystic fibrosis nonsense mutation chloride channel readthrough therapy CFTR rescue Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	cystic fibrosis nonsense mutation chloride channel readthrough therapy CFTR rescue Biology (General) QH301-705.5 Chemistry QD1-999 Arianna Venturini Anna Borrelli Ilaria Musante Paolo Scudieri Valeria Capurro Mario Renda Nicoletta Pedemonte Luis J. V. Galietta Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene
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 <i>CFTR</i> 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.
format	article
author	Arianna Venturini Anna Borrelli Ilaria Musante Paolo Scudieri Valeria Capurro Mario Renda Nicoletta Pedemonte Luis J. V. Galietta
author_facet	Arianna Venturini Anna Borrelli Ilaria Musante Paolo Scudieri Valeria Capurro Mario Renda Nicoletta Pedemonte Luis J. V. Galietta
author_sort	Arianna Venturini
title	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_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_sort	comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the cftr gene
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/90cee40555d5412c8ee9842eafddf790
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Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

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