Optical detection of distal lung enzyme activity in human inflammatory lung disease.

Alicia Megia-Fernandez, Adam Marshall, Ahsan R Akram, Beth Mills, Sunay Chankeshwara, Emma Scholefield, Amy Miele, Bruce McGorum, Chesney Michaels, Nathan Knighton, Tom Vercauteren, Francois Lacombe, Veronique Dentan, Annya Bruce, Joanne Mair, Robert Hitchcock, Nik Hirani, Chris Haslett, Mark Bradley, Kevin Dhaliwal

Research output: Contribution to journalArticlepeer-review

Abstract

Objective and Impact Statement: There is a need to develop platforms delineating inflammatory biology of the distal human lung. We describe a platform technology approach to detect in situ enzyme activity and observe drug inhibition in the distal human lung using a combination of matrix metalloproteinase (MMP) optical reporters, fibered confocal fluorescence microscopy (FCFM) and a bespoke delivery device. Introduction: The development of new therapeutic agents is hindered by the lack of in vivo in situ experimental methodologies that can rapidly evaluate biological activity or drug-target engagement in patients.
Methods: We lead optimised a novel highly quenched optical molecular reporter of enzyme activity (FIB One) and developed a translational pathway for in-human assessment. Results: We demonstrate specificity for Matrix Metalloproteases (MMPs) 2, 9 and 13, probe de34 quenching within physiological levels of MMP and feasibility of imaging within whole lung models in pre-clinical settings. Subsequently, in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease, we demonstrate through FCFM, MMP activity in the alveolar space measured through FIB One fluorescence increase (with pharmacological inhibition).
Conclusion: This translational in situ approach enables a new methodology to demonstrate active drug target effects of the distal lung and consequently may inform therapeutic drug development pathways.
Original languageEnglish
JournalBiomedical Engineering Frontiers
DOIs
Publication statusPublished - 7 Apr 2021

Keywords

  • optical imaging
  • Matrix Metalloproteinase
  • FCFM
  • lung disease
  • Translational Imaging
  • First-in-human study

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