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

项目总结 新冠肺炎疫情极大地凸显了急性呼吸窘迫尚未得到满足的严重需求 综合症(ARDS)，包括缺乏对ARDS易感性和健康差异的关键遗传见解，以及 缺乏FDA批准的有效药物干预措施来解决ARDS死亡率问题。阿兹 表型异质性、炎症调节失调的复杂性以及缺乏可预测的生物标记物 都是导致ARDS治疗临床试验失败的原因。我们之前发现了一种错义基因变异， (Met62Ile)位于P-选择素配体基因(SELPLG)，编码P-选择素糖蛋白配体1 (PSGL1)与黑人ARDS易感性增加有关。PSGL1/P-选择素相互作用 由于这种炎症途径的关键作用，在生物学上是ARDS治疗的一个高度可信的靶点 在中性粒细胞(PMN)的白细胞运输、血小板聚集和血栓形成中。在已发表的研究中， 呼吸机(VILI)和脂多糖(LPS)诱导的SELPLG表达显著增加 肺损伤可通过SELPLG击倒或PSGL1抑制而显著减轻。我们最近做了 结果显示，脓毒症、急性呼吸窘迫综合征和新冠肺炎患者的血浆PSGL1和P-选择素水平显著升高 肺炎患者与对照组比较。我们和其他人已经确定了相关的SELPLG和SELP变体 与血浆PSGL1升高相关的ARDS风险和死亡率以及SELPLG和SELP变异 和P-选择素。这些初步数据表明，SELPLG/SELP变异体与升高的 血浆PSGL1/P-选择素水平可被整合到基于遗传学的生物标记物风险评分(GBRS)中 阿兹。我们推测，基于PSGL1/P-选择素途径的GBR可能定义了世卫组织的风险亚群 是针对PSGL1/P-选择素相互作用(内型)的临床试验的极佳候选者。 集中招募这一有风险的ARDS亚组将代表一种新的ARDS临床试验方法 设计。特定目标(SA)#1将定义血浆PSGL-1和P-选择素水平的遗传调节，使用 数据和样本来自NHLBI ARDSNet肺泡研究(539名患者)。孟德尔式的创新使用 随机化和中介分析将允许我们生成基于遗传学的生物标记物风险分数 ARDS最初聚焦于10个SELPLG/22 SEP SNP，发现可能预测血浆PSGL1和P-SNP 分别为选择素水平。SA#2将利用来自NIAID免疫表型评估的生物标记物 在一项新冠肺炎队列研究(&gt；1000名患者)中，验证了GBRS在预测风险和死亡率方面的有效性 来自新冠肺炎相关的急性呼吸窘迫综合征。SA#3将评估靶向PSGL-1/P-选择素的治疗效果 利用FDA IND-IND建立的小动物和大动物临床前ARDS/VILI模型的相互作用 批准的P-选择素抑制剂，重组串联PSGL1免疫球蛋白融合分子(TSGL-Ig)。 成功完成这一高度翻译的R01赠款将产生一种新的“关注点”药物遗传学 TSGL-Ig的创新设计的人类ARDS临床试验将利用浓缩工具。

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.