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

Author:

McCarron Alexandra1ORCID,Ling Kak-Ming2,Montgomery Samuel2,Martinovich Kelly3,Cmielewski Patricia4ORCID,Rout-Pitt Nathan5,Kicic Anthony2,Parsons David6ORCID,Donnelley Martin7ORCID

Affiliation:

1. The University of Adelaide

2. Telethon Kids Institute

3. Murdoch University

4. WCH

5. Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, 72 King William Road, North Adelaide SA 5006, Australia

6. SPring-8 Synchrotron

7. University of Adelaide

Abstract

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 a separate group of Phe508del and KO airway epithelial cells were treated with LV-CFTR followed by differentiation. 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.

Publisher

Springer Science and Business Media LLC

Reference26 articles.

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4. Characterization of two rat models of cystic fibrosis-KO and F508del CFTR-Generated by Crispr-Cas9;Dreano E,2019

5. Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets;Sun X;Am J Respir Cell Mol Biol,2013

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