The development of novel strategies to modulate epithelial sodium channel (ENaC) activity in chronic obstructive pulmonary disease (COPD)

  • Emma Carroll

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Impaired mucociliary clearance (MCC) which leads to infection, inflammation, and progressive lung damage is a hallmark of the chronic bronchitis (CB) phenotype in COPD, and the hydration status of the airways has been indicated as the main factor affecting this disorder. Inhibition of ENaC function in the airways has become an attractive therapeutic strategy to counteract airway surface dehydration and defective MCC. Thus, the overarching aim of this research was to investigate the potential of two novel strategies to modulate ENaC activity.

A CAP inhibitor-based approach utilising natural peptide-based inhibitors, derived from amphibian skin secretions, revealed two lead compounds - QUB- 1916 and QUB-2136. Both peptides were found to exhibit potent low-micromolar or nanomolar inhibitory activity against human airway trypsin-like (HAT) protease, matriptase, and prostasin. QUB-2136 was capable of inhibiting amiloride short-circuit current to a greater extent and for a longer period of time when compared to QUB-1916. However, further evaluation of QUB-2136 indicated that structural modifications would be necessary in order for this peptide to have utility in functional ASL height, MCC and in vivo studies.

A second genomic approach investigated the ability of the QUB-patented RALA peptide drug delivery system to transport an αENaC small interfering RNA (siRNA) cargo into primary bronchial epithelial cells (PBECs). RALA/siRNA nanoparticles were well-tolerated by submerged PBECs and transfection of cells led to a high level of αENaC mRNA knockdown. Whilst local delivery to PBEC cultures at air-liquid interface (ALI) appeared promising, it is likely that nanoparticle modification will be required to further enhance silencing of αENaC for therapeutic benefit. Future work to develop a more optimised airway epithelial cell-targeted version of RALA nanocomplexes for the effective targeting of ENaC via local airway delivery holds significant potential.

Thesis embargoed until 31 July 2024.
Date of AwardJul 2022
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsSpecial EU Programmes Body
SupervisorLorraine Martin (Supervisor), Fionnuala Lundy (Supervisor) & Lorcan McGarvey (Supervisor)

Keywords

  • ENaC
  • COPD
  • chronic bronchitis
  • amphibian skin secretion
  • RALA peptide
  • siRNA
  • CPP
  • nanoparticles
  • trypsin-like proteases
  • electrophysiology
  • primary bronchial epithelial cells

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