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      Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis

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          Cystic fibrosis (CF) is a life-limiting autosomal recessive disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Management of CF has traditionally relied upon managing complications of CFTR protein dysfunction and this has led to a steady improvement in survival of CF patients. However, the landscape of CF care has changed substantially over the last decade with the discovery of CFTR modulators that aim to increase or potentially restore the function of the disease-causing CFTR protein. This narrative review summarizes the development of CFTR therapies so far with emphasis on tezacaftor/ivacaftor combination therapy. We have also summarized the Phase II results of triple combination therapy which promises an effective CFTR modulator therapy for more than 90% of CF patients.

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          Most cited references 22

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          Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.

          Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7. Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF. The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding. A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
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            CFTR function and prospects for therapy.

             John Riordan (2007)
            Mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) epithelial anion channel cause cystic fibrosis (CF). The multidomain integral membrane glycoprotein, a member of the adenine nucleotide-binding cassette (ABC) transporter family, conserved in metazoan salt-transporting tissues, is required to control ion and fluid homeostasis on epithelial surfaces. This review considers different therapeutic strategies that have arisen from knowledge of CFTR structure and function as well as its biosynthetic processing, intracellular trafficking, and turnover.
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              CFTR as a cAMP-dependent regulator of sodium channels.

              Cystic fibrosis transmembrane regulator (CFTR), the gene product that is mutated in cystic fibrosis (CF) patients, has a well-recognized function as a cyclic adenosine 3',5'-monophosphate (cAMP)-regulated chloride channel, but this property does not account for the abnormally high basal rate and cAMP sensitivity of sodium ion absorption in CF airway epithelia. Expression of complementary DNAs for rat epithelial Na+ channel (rENaC) alone in Madin Darby canine kidney (MDCK) epithelial cells generated large amiloride-sensitive sodium currents that were stimulated by cAMP, whereas coexpression of human CFTR with rENaC generated smaller basal sodium currents that were inhibited by cAMP. Parallel studies that measured regulation of sodium permeability in fibroblasts showed similar results. In CF airway epithelia, the absence of this second function of CFTR as a cAMP-dependent regulator likely accounts for abnormal sodium transport.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                22 August 2019
                : 15
                : 1029-1040
                [1 ]Department of Respiratory Medicine, Hull University Teaching Hospitals NHS Trust , Cottingham HU16 5JQ, UK
                Author notes
                Correspondence: Shoaib FaruqiDepartment of Respiratory Medicine, University of Hull and Hull and York Medical School, Hull University Teaching Hospitals NHS Trust , Castle Hill Hospital, Castle Road, CottinghamHU16 5JQ, UKTel +44 148 262 6706 Email Shoaib.Faruqi@hey.nhs.uk

                These authors contributed equally to this work

                © 2019 Shiferaw and Faruqi.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Tables: 5, References: 44, Pages: 12


                triple therapy, tezacaftor, ivacaftor, cftr potentiators, cftr modulators, cystic fibrosis


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