Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9421525 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5462 (Electronic) Linking ISSN: 09697128 NLM ISO Abbreviation: Gene Ther Subsets: MEDLINE
    • Publication Information:
      Publication: London : Nature Publishing Group
      Original Publication: Houndmills, Basingstoke, Hampshire, UK : Macmillan Press Ltd., c1994-
    • Subject Terms:
      Cystic Fibrosis*/therapy ; Cystic Fibrosis*/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator*/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism ; Genetic Therapy*/methods ; Lentivirus*/genetics ; Genetic Vectors*/genetics ; Genetic Vectors*/administration & dosage ; Quinolones*/pharmacology ; Quinolones*/therapeutic use ; Disease Models, Animal* ; Aminophenols*/pharmacology ; Aminophenols*/therapeutic use ; Benzodioxoles*/pharmacology ; Benzodioxoles*/therapeutic use; Animals ; Rats ; Indoles/pharmacology ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Trachea/metabolism ; Pyrroles/pharmacology ; Pyrroles/therapeutic use ; Drug Combinations ; Humans ; Epithelial Cells/metabolism ; Rats, Sprague-Dawley ; Pyridines ; Pyrrolidines ; Quinolines
    • Abstract:
      Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.
      Competing Interests: Competing interests The authors declare no competing interests.
      (© 2024. The Author(s).)
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    • Grant Information:
      GNT1160011 Department of Health | National Health and Medical Research Council (NHMRC); DONNEL21GO Cystic Fibrosis Foundation (CF Foundation)
    • Accession Number:
      126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
      0 (Quinolones)
      0 (Aminophenols)
      0 (Benzodioxoles)
      0 (Indoles)
      0 (Pyrazoles)
      0 (Pyrroles)
      0 (Drug Combinations)
      RRN67GMB0V (elexacaftor)
      0 (elexacaftor, ivacaftor, tezacaftor drug combination)
      0 (Pyridines)
      0 (Pyrrolidines)
      0 (Quinolines)
    • Publication Date:
      Date Created: 20240825 Date Completed: 20241120 Latest Revision: 20241122
    • Publication Date:
      20241122
    • Accession Number:
      PMC11576507
    • Accession Number:
      10.1038/s41434-024-00480-y
    • Accession Number:
      39183346