# Increasing the Success of ARDS Therapeutic Clinical Trials: Novel Trial Design and Targeting of the P-selectin Pathway

> **NIH NIH R56** · UNIVERSITY OF ARIZONA · 2022 · $529,354

## Abstract

PROJECT SUMMARY
The COVID-19 pandemic has dramatically highlighted the serious unmet needs of acute respiratory distress
syndrome (ARDS) including the lack of key genetic insights into ARDS susceptibility and health disparities, and
the absence of effective FDA-approved pharmacologic interventions that address ARDS mortality. ARDS
phenotype heterogeneity, the complexity of dysregulated inflammation, and the absence of predictive biomarkers
have all contributed to failed ARDS therapeutic clinical trials. We previously identified a missense genetic variant,
(Met62Ile) located in the selectin P ligand gene (SELPLG), which encodes for P-selectin glycoprotein ligand 1
(PSGL1) that was associated with increased susceptibility to ARDS in Blacks. PSGL1/P-selectin interactions
are a highly biologically-plausible target for ARDS therapies due to the critical role of this inflammatory pathway
in polymorphonuclear (PMN) leukocyte trafficking, platelet aggregation, and thrombosis. In published studies,
SELPLG expression was significantly increased with ventilator (VILI)- and lipopolysaccharide (LPS)-induced
lung injury that was significantly attenuated by either SELPLG knock down or PSGL1 inhibition. We have recently
shown that plasma PSGL1 and P-selectin levels are significantly elevated in sepsis, ARDS, and COVID-19
pneumonia patients compared to controls. We and others have identified SELPLG and SELP variants associated
with ARDS risk and mortality and SELPLG and SELP variants that are associated with elevated plasma PSGL1
and P-selectin. These preliminary data suggest that the combination of SELPLG/SELP variants with elevated
plasma PSGL1/P-selectin levels may be integrated into a genetics-based biomarker risk score (GBRS) for
ARDS. We speculate that a PSGL1 /P-Selectin pathway-based GBRS may define an ‘at risk’ subgroup of who
are excellent candidates for inclusion in a clinical trial targeting PSGL1 /P-Selectin interactions (endotype).
Focused recruitment of this “at risk” ARDS subgroup would represent a novel approach to ARDS clinical trial
design. Specific Aim (SA) #1 will define the genetic regulation of plasma PSGL-1 and P-selectin levels using
data and samples from the NHLBI ARDSnet ALVEOLI study (539 patients). Innovative use of Mendelian
Randomization and mediation analyses will allow us to generate the genetics-based biomarker risk score for
ARDS initially focusing on 10 SELPLG/22 SELP SNPs identified that potentially predict plasma PSGL1 and P-
selectin levels, respectively. SA #2 will leverage biospecimens from the NIAID Immunophenotyping Assessment
in a COVID-19 Cohort (IMPACC) study (>1000 patients) to validate GBRS utility in predicting risk of and mortality
from COVID-19-associated ARDS. SA #3 will assess the therapeutic efficacy of targeting PSGL-1/P-selectin
interactions in well-established small and large animal preclinical ARDS/VILI models utilizing the FDA IND-
approved P-selectin inhibitor, recombinant tandem PSGL1 immunoglobulin fus...

## Key facts

- **NIH application ID:** 10683789
- **Project number:** 1R56HL160907-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Christian Bime
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $529,354
- **Award type:** 1
- **Project period:** 2022-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683789

## Citation

> US National Institutes of Health, RePORTER application 10683789, Increasing the Success of ARDS Therapeutic Clinical Trials: Novel Trial Design and Targeting of the P-selectin Pathway (1R56HL160907-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10683789. Licensed CC0.

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