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Gene therapy for cystic fibrosis: Challenges and prospects

Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the e...

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Autores principales: Sui, Hongshu, Xu, Xinghua, Su, Yanping, Gong, Zhaoqing, Yao, Minhua, Liu, Xiaocui, Zhang, Ting, Jiang, Ziyao, Bai, Tianhao, Wang, Junzuo, Zhang, Jingjun, Xu, Changlong, Luo, Mingjiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592762/
https://www.ncbi.nlm.nih.gov/pubmed/36304167
http://dx.doi.org/10.3389/fphar.2022.1015926
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author Sui, Hongshu
Xu, Xinghua
Su, Yanping
Gong, Zhaoqing
Yao, Minhua
Liu, Xiaocui
Zhang, Ting
Jiang, Ziyao
Bai, Tianhao
Wang, Junzuo
Zhang, Jingjun
Xu, Changlong
Luo, Mingjiu
author_facet Sui, Hongshu
Xu, Xinghua
Su, Yanping
Gong, Zhaoqing
Yao, Minhua
Liu, Xiaocui
Zhang, Ting
Jiang, Ziyao
Bai, Tianhao
Wang, Junzuo
Zhang, Jingjun
Xu, Changlong
Luo, Mingjiu
author_sort Sui, Hongshu
collection PubMed
description Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.
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spelling pubmed-95927622022-10-26 Gene therapy for cystic fibrosis: Challenges and prospects Sui, Hongshu Xu, Xinghua Su, Yanping Gong, Zhaoqing Yao, Minhua Liu, Xiaocui Zhang, Ting Jiang, Ziyao Bai, Tianhao Wang, Junzuo Zhang, Jingjun Xu, Changlong Luo, Mingjiu Front Pharmacol Pharmacology Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects. Frontiers Media S.A. 2022-10-11 /pmc/articles/PMC9592762/ /pubmed/36304167 http://dx.doi.org/10.3389/fphar.2022.1015926 Text en Copyright © 2022 Sui, Xu, Su, Gong, Yao, Liu, Zhang, Jiang, Bai, Wang, Zhang, Xu and Luo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sui, Hongshu
Xu, Xinghua
Su, Yanping
Gong, Zhaoqing
Yao, Minhua
Liu, Xiaocui
Zhang, Ting
Jiang, Ziyao
Bai, Tianhao
Wang, Junzuo
Zhang, Jingjun
Xu, Changlong
Luo, Mingjiu
Gene therapy for cystic fibrosis: Challenges and prospects
title Gene therapy for cystic fibrosis: Challenges and prospects
title_full Gene therapy for cystic fibrosis: Challenges and prospects
title_fullStr Gene therapy for cystic fibrosis: Challenges and prospects
title_full_unstemmed Gene therapy for cystic fibrosis: Challenges and prospects
title_short Gene therapy for cystic fibrosis: Challenges and prospects
title_sort gene therapy for cystic fibrosis: challenges and prospects
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592762/
https://www.ncbi.nlm.nih.gov/pubmed/36304167
http://dx.doi.org/10.3389/fphar.2022.1015926
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