Cargando…

Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein fun...

Descripción completa

Detalles Bibliográficos
Autores principales: Fajac, Isabelle, Sermet, Isabelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534516/
https://www.ncbi.nlm.nih.gov/pubmed/34685773
http://dx.doi.org/10.3390/cells10102793
_version_ 1784587571739754496
author Fajac, Isabelle
Sermet, Isabelle
author_facet Fajac, Isabelle
Sermet, Isabelle
author_sort Fajac, Isabelle
collection PubMed
description Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.
format Online
Article
Text
id pubmed-8534516
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-85345162021-10-23 Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators Fajac, Isabelle Sermet, Isabelle Cells Review Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients. MDPI 2021-10-19 /pmc/articles/PMC8534516/ /pubmed/34685773 http://dx.doi.org/10.3390/cells10102793 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 Review
Fajac, Isabelle
Sermet, Isabelle
Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title_full Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title_fullStr Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title_full_unstemmed Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title_short Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators
title_sort therapeutic approaches for patients with cystic fibrosis not eligible for current cftr modulators
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534516/
https://www.ncbi.nlm.nih.gov/pubmed/34685773
http://dx.doi.org/10.3390/cells10102793
work_keys_str_mv AT fajacisabelle therapeuticapproachesforpatientswithcysticfibrosisnoteligibleforcurrentcftrmodulators
AT sermetisabelle therapeuticapproachesforpatientswithcysticfibrosisnoteligibleforcurrentcftrmodulators