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      Strategies for the etiological therapy of cystic fibrosis

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          Abstract

          Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies.

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          Most cited references129

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          Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.

          Single murine and human intestinal stem cells can be expanded in culture over long time periods as genetically and phenotypically stable epithelial organoids. Increased cAMP levels induce rapid swelling of such organoids by opening the cystic fibrosis transmembrane conductor receptor (CFTR). This response is lost in organoids derived from cystic fibrosis (CF) patients. Here we use the CRISPR/Cas9 genome editing system to correct the CFTR locus by homologous recombination in cultured intestinal stem cells of CF patients. The corrected allele is expressed and fully functional as measured in clonally expanded organoids. This study provides proof of concept for gene correction by homologous recombination in primary adult stem cells derived from patients with a single-gene hereditary defect. Copyright © 2013 Elsevier Inc. All rights reserved.
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            A functional CFTR assay using primary cystic fibrosis intestinal organoids.

            We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.
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              Cystic fibrosis genetics: from molecular understanding to clinical application.

              The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.
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                Author and article information

                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group
                1350-9047
                1476-5403
                November 2017
                22 September 2017
                1 November 2017
                : 24
                : 11
                : 1825-1844
                Affiliations
                [1 ]Department of Health Sciences, University of Eastern Piedmont , Novara 28100, Italy
                [2 ]European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan 20132, Italy
                [3 ]Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University Naples 80131, Italy
                [4 ]Equipe11 labellisée Ligue Nationale Contrele Cancer, Centre de Recherche des Cordeliers , Paris, France
                [5 ]INSERM U1138, Centre de Recherche des Cordeliers , Paris, France
                [6 ]Université Paris Descartes , Paris, France
                [7 ]Metabolomics and Cell Biology Platforms, Institut Gustave Roussy , Villejuif, France
                [8 ]Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP , Paris, France
                [9 ]Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital , Stockholm 17176, Sweden
                Author notes
                [* ]European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan 20132, Italy. Tel: +393 311 313 941; Fax: +390226434328, E-mail: maiuri.luigi@ 123456hsr.it
                [* ]Equipe 11 labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers , Paris 75006, France. Tel: +3301 44 27 76 67; Fax: +3301 44 27 76 74; E-mail: kroemer@ 123456orange.fr
                Article
                cdd2017126
                10.1038/cdd.2017.126
                5635223
                28937684
                74a2fc9d-13b5-4bdd-8f8c-0e0949186aba
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 27 March 2017
                : 22 June 2017
                : 23 June 2017
                Categories
                Review

                Cell biology
                Cell biology

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