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

提高 ARDS 治疗临床试验的成功率：P-选择素途径的新颖试验设计和靶向

• 批准号: 10683789
• 负责人: Christian Bime
• 金额: $ 52.94万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683789
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Address; Animals; Attenuated; Binding Sites; Biological Markers; Black Populations; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 pneumonia; COVID-19/ARDS; Clinical Trials; Clinical Trials Design; Cohort Studies; Critical Care; Critical Illness; Data; Data Set; FDA approved; Family suidae; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Glycoproteins; Goals; Grant; Heterogeneity; Human; Immune response; Immunoglobulins; Immunophenotyping; Inflammation; Inflammatory; Intervention; Leukocyte Trafficking; Ligands; Lipopolysaccharides; Measurement; Mediation; Mendelian randomization; Minor; Modeling; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; P-Selectin; P-selectin ligand protein; Pathway interactions; Patients; Persons; Pharmacogenetics; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Platelet aggregation; Play; Pre-Clinical Model; Predisposition; Publishing; Rattus; Recombinants; Regulation; Resources; Risk; Role; SELP gene; Sampling; Subgroup; Survivors; Systems Biology; Therapeutic; Therapeutic Clinical Trial; Thrombosis; Tidal Volume; Treatment Efficacy; United States National Institutes of Health; Variant; Ventilator; Virus Diseases; base; cohort; design; genetic predictors; genetic variant; genome wide methylation; health disparity; in silico; in vivo; inhibitor; innovation; insight; knock-down; lung injury; mortality; mouse model; neutrophil; novel; novel strategies; novel therapeutic intervention; patient subsets; point of care; pre-clinical; predictive marker; promoter; recruit; sepsis induced ARDS; success; therapeutic target; tool; trafficking; transcription factor; trial design; validation studies

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.

项目摘要 2019冠状病毒病大流行突显了急性呼吸窘迫的严重未满足需求 综合征（ARDS），包括缺乏对ARDS易感性和健康差异的关键遗传见解，以及 缺乏有效的FDA批准的药物干预措施来解决ARDS死亡率。ARDS 表型异质性、炎症失调的复杂性和缺乏预测性生物标志物 都导致了ARDS治疗临床试验的失败。我们之前发现了一种错义基因变异， （Met 62 Ile）位于选择素P配体基因（SELPLG）中，其编码P-选择素糖蛋白配体1 （PSGL 1）与黑人对ARDS的易感性增加有关。PSGL 1/P-选择素相互作用 由于这种炎症途径的关键作用， 在多形核白细胞（PMN）白细胞运输、血小板聚集和血栓形成中。在已发表的研究中， SELPLG的表达在呼吸机（VILI）和脂多糖（LPS）诱导的 通过SELPLG敲低或PSGL 1抑制显著减弱的肺损伤。我们最近 显示血浆PSGL 1和P-选择素水平在脓毒症、ARDS和COVID-19中显著升高 肺炎患者与对照组相比。我们和其他人已经确定了SELPLG和SELP变异相关 ARDS风险和死亡率以及与血浆PSGL 1升高相关的SELPLG和SELP变异 和P-选择素。这些初步数据表明，SELPLG/SELP变体与升高的细胞因子的组合， 血浆PSGL 1/P-选择素水平可以整合到基于遗传学的生物标志物风险评分（GBRS）中， ARDS。我们推测，基于PSGL 1/P-选择素途径的GBRS可能定义了一个“处于危险中”的亚组， 是纳入靶向PSGL 1/P-选择素相互作用（内型）的临床试验的优秀候选者。 集中招募这种“高危”ARDS亚组将代表一种新的ARDS临床试验方法 设计特定目的（SA）#1将使用以下方法定义血浆PSGL-1和P-选择素水平的遗传调节： 数据和样本来自NHLBI ARDSnet ALVEOLI研究（539例患者）。孟德尔式的创新应用 随机化和中介分析将使我们能够生成基于遗传学的生物标志物风险评分， ARDS最初集中在10个SELPLG/22个SELP SNP上，这些SNP被鉴定为可能预测血浆PSGL 1和P- 选择素水平。SA #2将利用来自NIAID免疫表型评估的生物标本 在一项COVID-19队列（IMPACC）研究（>1000例患者）中，验证GBRS在预测死亡风险和死亡率方面的实用性 COVID-19相关的ARDS。SA #3将评估靶向PSGL-1/P-选择素的治疗效果 在使用FDA IND的成熟的小型和大型动物临床前ARDS/VILI模型中的相互作用- 批准的P-选择素抑制剂，重组串联PSGL 1免疫球蛋白融合分子（TSGL-Ig）。 成功完成这一高度转化的R 01资助将产生一种新的“护理点”药物遗传学 在TSGL-Ig的创新设计的人类ARDS临床试验中利用富集工具。