Royal College of Surgeons in Ireland
Precise_targeting_of_miRNA_sites_restores_CFTR_activity_in_CF_bronchial.pdf (3.65 MB)
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Precise targeting of miRNA sites restores CFTR activity in CF bronchial epithelial cells.

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posted on 2020-12-18, 16:59 authored by Chiara De SantiChiara De Santi, Elena Fernandez Fernandez, Rachel GaulRachel Gaul, Sebastian Vencken, Arlene Glasgow, Irene OglesbyIrene Oglesby, Killian HurleyKillian Hurley, Finn Hawkins, Nilay Mitash, Fangping Mu, Rana Raoof, David HenshallDavid Henshall, Meritxell B. Cutrona, Jeremy C. Simpson, Brian HarveyBrian Harvey, Barry Linnane, Paul McNallyPaul McNally, Sally-Ann CryanSally-Ann Cryan, Ronan MacLoughlinRonan MacLoughlin, Agnieszka Swiatecka-Urban, Catherine GreeneCatherine 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)



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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)