Gene therapy for cystic fibrosis: new tools for precision medicine

Lee, Jin-A; Cho, Alex; Huang, Elena N.; Xu, Yiming; Quach, Henry; Wong, Amy P.

doi:10.1186/s12967-021-03099-4

Cited by 41 publications

(37 citation statements)

References 152 publications

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“…Gene therapy and gene editing offers great hope for the treatment of a monogenic disease such as CF as these approaches would mean a potentially permanent cure (reviewed in [ 152 , 153 ]). In the case of gene therapy, although preclinical studies evidenced some success in cell and animal models, results from clinical studies have evidenced several difficulties, namely targeting the correct cell population in a proportion enough to translate into clinical benefit or overcoming the mucus barrier, limiting the number of studies that have in fact aimed at developing gene therapy approaches for CF patients [ 154 ].…”

Section: Molecular Mechanisms Of Disease – How Do Cftr Mutations Caus...mentioning

confidence: 99%

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Farinha

Callebaut

2022

Bioscience Reports

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Cystic Fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse – ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches.

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Section: Molecular Mechanisms Of Disease – How Do Cftr Mutations Caus...mentioning

confidence: 99%

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Farinha

Callebaut

2022

Bioscience Reports

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“…Organoids can serve as a good platform for evaluating gene therapy, in which gene editing technologies are used to repair genetic deficiencies in patients. 311 , 436 , 437 For example, the use of CRISPR gene editing technology to correct CFTR mutations in intestinal organoids of CF patients has shown that gene repair can correct the CFTR locus in patient-derived CF organoids and restore the normal response of organoids to forskolin treatment. 438 Organoids can also be used as an alternative test model for FMT therapeutic strategies.…”

Section: Digestive System Organoid Models and Precision And Personali...mentioning

confidence: 99%

Applications of human organoids in the personalized treatment for digestive diseases

Wang

Guo

Jin

et al. 2022

Sig Transduct Target Ther

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Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

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“…CRISPR-based gene editing approaches have been explored to correct certain CFTR mutations in cultured airway basal cells, iPS cells, and advanced cellular models, such as organoid cultures derived from patients with CF ( Ensinck et al, 2021 ; Lee et al, 2021 ). HDR-based CFTR corrections have demonstrated the capacities to correct missense or nonsense mutations in exons, to ablate splice mutations, and to insert “super exons” from the DNA donor template provided along with the CRISPR components ( Schwank et al, 2013 ; Firth et al, 2015 ).…”

Section: Gene Editingmentioning

confidence: 99%

“…New animal models and more efficacious gene transfer agents have been developed to move the field in the path to success. Several recent excellent review articles have summarized and discussed the lessons and achievements from the last 3 decades ( Cooney et al, 2018a ; Donnelley and Parsons, 2018 ; Yan et al, 2019 ; Tang et al, 2020a ; Allan et al, 2021 ; Lee et al, 2021 ). In this review, after a brief description of the lessons learned from the previous unsuccessful clinical trials of CF gene therapy in an alignment with recent progress in animal models and viral vectors as tools of gene delivery, we will focus on the major challenges to the implementation of the gene therapy for CF lung disease.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for cystic fibrosis: Challenges and prospects

Sui

et al. 2022

Front. Pharmacol.

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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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Gene therapy for cystic fibrosis: new tools for precision medicine

Cited by 41 publications

References 152 publications

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Applications of human organoids in the personalized treatment for digestive diseases

Gene therapy for cystic fibrosis: Challenges and prospects

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