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Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Wren E. Michaels, Robert J. Bridges, Michelle L. Hastings
doi: https://doi.org/10.1101/2020.05.12.089417
Wren E. Michaels
1Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Science and Medicine, North Chicago, IL, 60064, United States of America
2School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Science and Medicine, North Chicago, IL, 60064, United States of America
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Robert J. Bridges
1Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Science and Medicine, North Chicago, IL, 60064, United States of America
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  • For correspondence: michelle.hastings@rosalindfranklin.edu robert.bridges@rosalindfranklin.edu
Michelle L. Hastings
1Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Science and Medicine, North Chicago, IL, 60064, United States of America
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  • For correspondence: michelle.hastings@rosalindfranklin.edu robert.bridges@rosalindfranklin.edu
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ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in more than 15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10kbC>T), which creates a new 5’ splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 14, 2020.
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Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells
Wren E. Michaels, Robert J. Bridges, Michelle L. Hastings
bioRxiv 2020.05.12.089417; doi: https://doi.org/10.1101/2020.05.12.089417
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Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells
Wren E. Michaels, Robert J. Bridges, Michelle L. Hastings
bioRxiv 2020.05.12.089417; doi: https://doi.org/10.1101/2020.05.12.089417

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