In the research article“Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease”[1],the data availability statement was inadvertently omitted by the publisher.This has now been corrected ...In the research article“Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease”[1],the data availability statement was inadvertently omitted by the publisher.This has now been corrected in the PDF and HTML(full text).展开更多
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 dr...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 the biological activity or drug-target engagement in patients.Methods.We 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 the specificity for matrix metalloproteases(MMPs)2,9,and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical settings.Subsequently,in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease,we demonstrate,through FCFM,the 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.展开更多
文摘In the research article“Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease”[1],the data availability statement was inadvertently omitted by the publisher.This has now been corrected in the PDF and HTML(full text).
基金supported by the Medical Research Council(under the Developmental Pathway Funding Scheme grant number MR/J014702)the Engineering and Physical Sciences Research Council(EP/K03197X/1,EP/R005257/1,and NS/A000049/1)+3 种基金the Wellcome Trust(203148/Z/16/Z)AA is supported by a Cancer Research UK Clinician Scientist Fellowship(A24867)TV is supported by a Medtronic/Royal Academy of Engineering Research Chair(RCSRF1819\7\34)The research leading to these results has received funding from the European Union Seventh Framework Programme FP72012 under grant agreement No.326465(AMF).
文摘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 the biological activity or drug-target engagement in patients.Methods.We 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 the specificity for matrix metalloproteases(MMPs)2,9,and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical settings.Subsequently,in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease,we demonstrate,through FCFM,the 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.
