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

项目总结

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 fusion molecule (TSGL-Ig). Successful completion of this highly translational R01 grant will generate a novel ‘point of care’ pharmacogenetic enrichment tool to be leveraged in innovatively designed human ARDS clinical trials of TSGL-Ig.