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Precise targeting of miRNA sites restores CFTR activity in CF bronchial epithelial cells.

journal contribution
posted on 05.02.2021, 00:33 by Chiara De Santi, Elena Fernandez Fernandez, Rachel Gaul, Sebastian Vencken, Arlene Glasgow, Irene Oglesby, Killian Hurley, Finn Hawkins, Nilay Mitash, Fangping Mu, Rana Raoof, David Henshall, Meritxell B. Cutrona, Jeremy C. Simpson, Brian Harvey, Barry Linnane, Paul McNally, Sally-Ann Cryan, Ronan MacLoughlin, Agnieszka Swiatecka-Urban, Catherine Greene
MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3' untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3' UTR 298-305:miR-145-5p or 166-173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.


Cystic Fibrosis Foundation Therapeutics (GREENE15XXO)

National Children’s Research Centre (C/13/1)

The National Institutes of Health (R01HL144539)

Cystic Fibrosis Foundation (SWIATE18G0)

Horizon2020 MSCA-IF (award 707771 GENDER-CF)

Irish Research Council (GOIPG/2015/2393)



This article is also available from https://www.cell.com

Published Citation

De Santi C, Fernández Fernández E, Gaul R, Vencken S, Glasgow A, Oglesby IK, Hurley K, Hawkins F, Mitash N, Mu F, Raoof R, Henshall DC, Cutrona MB, Simpson JC, Harvey BJ, Linnane B, McNally P, Cryan SA, MacLoughlin R, Swiatecka-Urban A, Greene CM. Precise targeting of miRNA sites restores CFTR activity in CF bronchial epithelial cells. Molecular Therapy. 2020:28(4):1190-1199

Publication Date

5 February 2020

PubMed ID



  • Clinical Microbiology
  • RCSI Tissue Engineering Group (TERG)
  • School of Pharmacy and Biomolecular Sciences
  • Paediatrics
  • Physiology and Medical Physics
  • Molecular Medicine
  • Medicine




  • Accepted Version (Postprint)