Stratified interventions in ARDS (EMINENT)
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
There is an urgent and unmet need to define disease pathogenesis in acute respiratory distress syndrome (ARDS), and to develop rapid diagnostics to aid patient stratification and support targeted intervention. This is a programmatic approach to define disease pathogenesis in ARDS, and to develop rapid diagnostics to aid patient stratification and support targeted intervention.
Technical Summary
WP1: ARDS: in whom to intervene? This will involve an unbiased informatics-based analysis of existing (HARP2, REST, MOSAIC, GALAXY, ARDS.NET) and new patient cohorts to define ARDS endotypes
WP2: ARDS: when to intervene? Undertake prospective analysis of trans-pulmonary cytokine, genomic/epigenomic and neutrophil and monocyte phenotyping/migration signatures, and novel imaging modalities (SPECT/CT, PET/CT) to define the optimal time for intervention in the above cohorts, and to develop rapid ('by lunchtime') diagnostic platforms. This WP will specifically test the concepts generated in well-established and highly refined animal, human lung slice and EVLP models of ALI
WP3: ARDS with what to intervene? The collaborative network established above will, together with GSK, be ideally positioned to deliver Phase IIa experimental POC studies, using existing assets in the specific subtypes identified; endpoints (e.g. vascular leak, cell migration, physiological indices, biomarkers) will be determined by the endotype under study
WP2: ARDS: when to intervene? Undertake prospective analysis of trans-pulmonary cytokine, genomic/epigenomic and neutrophil and monocyte phenotyping/migration signatures, and novel imaging modalities (SPECT/CT, PET/CT) to define the optimal time for intervention in the above cohorts, and to develop rapid ('by lunchtime') diagnostic platforms. This WP will specifically test the concepts generated in well-established and highly refined animal, human lung slice and EVLP models of ALI
WP3: ARDS with what to intervene? The collaborative network established above will, together with GSK, be ideally positioned to deliver Phase IIa experimental POC studies, using existing assets in the specific subtypes identified; endpoints (e.g. vascular leak, cell migration, physiological indices, biomarkers) will be determined by the endotype under study
Publications
Mehta P
(2020)
Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities.
in The Lancet. Respiratory medicine
| Description | EMINENT ARDS |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | This is a major multi-centre programmatic EMINENT project aimed at establishing the feasibility of identifying ARDS endotypes. The current funding covers costs for the first milestone of the project |
| Collaborator Contribution | The project is in its early stages but the partner made a major intellectual contribution to the drafting of the proposal. |
| Impact | Workpackage 1 is being led by the University of Cambridge as part of this initiative. Studies are currently still ongoing. |
| Start Year | 2017 |
| Description | EMINENT ARDS |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This is a major multi-centre programmatic EMINENT project aimed at establishing the feasibility of identifying ARDS endotypes. The current funding covers costs for the first milestone of the project |
| Collaborator Contribution | The project is in its early stages but the partner made a major intellectual contribution to the drafting of the proposal. |
| Impact | Workpackage 1 is being led by the University of Cambridge as part of this initiative. Studies are currently still ongoing. |
| Start Year | 2017 |
| Description | EMINENT ARDS WP2 |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The aim of this Workpackage is to define whether the ARDS endotypes are mechanistically discrete, or represent different phases of the same pathology, to refine and determine in greater depth our understanding of the pathophysiological pathways involved, in particular those that would be amenable to intervention with GSK portfolio drugs, and to develop rapid diagnostic platforms to allow such patients to be identified i.e. allowing the right drug to be given to the right patient at the right time. To address this, we will carry out deep-phenotyping of 100 patients with non-COVID related ARDS at three time-points to validate previous endotypes: My team at UCL will perform single cell RNA-Seq analysis of PBMCs obtained from patients with ARDS. |
| Collaborator Contribution | Our project partners will recruit ARDS patients and perform bulk RNA-Seq and cell phenotyping (CyToF) of circulating cell populations and measure levels of soluble serum biomarkers and relate clinical phenotype to outcomes. They will also leverage our unique links with ISARIC 4C/GenoMICC to determine the similarities and differences between the endotypes identified during non-COVID ARDS and those identified in COVID-19 ARDS. |
| Impact | Project still in set-up phase |
| Start Year | 2022 |
| Description | Outreach activities |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | In terms of further outreach activities, network partners have sought out synergies between the EMINENT network and multiple external stakeholders, including NIHR and ABPI and participated in EMINENT roadshows to promote EMINENT at the different University partner sites, focussing in particular on sites where project submission rates were felt to be lower than expected (for presentation see e.g.). The EMINENT programme has been presented at the following external events: • A joint workshop held on 9 March 2018 by the Academy of Medical Sciences and the Association of the British Pharmaceutical Industry (workshop report can be found at https://acmedsci.ac.uk/more/events/bridging-the-preclinical-clinical-boundary ) • A joint workshop titled "Delivering Experimental Medicine Research in Critical Care" held at King's College London in February 2018 coordinated by the National Institute for Health Research Clinical Research Network Critical Care Experimental Medicine Group (workshop report can be found at https://www.nihr.ac.uk/nihr-in-your-area/critical-care/documents/20180824_CCEM%20Workshop%20Report_FINAL.pdf ) • The NOCRI (NIHR Office for Clinical Research Infrastructure) Translational Research Collaboration for joint and inflammatory disease, comprising representatives from all NIHR BRCs with a rheumatology theme (UCL, Kings, IC, Oxford, Cambridge, Birmingham, Nottingham, Manchester, Leeds, Newcastle, Southampton) plus other relevant experimental medicine hubs (e.g. Barts). |
| Year(s) Of Engagement Activity | 2018 |
| Description | Science Day 2017 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | The Science day was a network-wide workshop which provided an opportunity for interaction and knowledge exchange between participating project staff and researchers from academic institutions and GSK |
| Year(s) Of Engagement Activity | 2017 |