Validation of a Genetic-based Biomarker Panel for Stratification of Mortality Risk in ARDS Patients

用于 ARDS 患者死亡风险分层的基于基因的生物标志物组的验证

• 批准号: 10645784
• 负责人: Christian Bime
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645784
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Angiopoietin-2; Attenuated; Biological Assay; Biological Markers; Black Populations; COVID-19 pandemic; COVID-19 pneumonia; COVID-19/ARDS; Clinical Trials; Clinical Trials Design; Data; Early treatment; Evaluation; FDA approved; Failure; Future; Genes; Genetic; Genomics; Genotype; Grant; Heterogeneity; Human; IL8 gene; Immunoglobulins; Induction of neuromuscular blockade; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Letters; Leukocyte Trafficking; Ligands; Lung; Mediation; Mendelian randomization; Modeling; Molecular; Monoclonal Antibodies; National Heart, Lung, and Blood Institute; Niacinamide; Outcome; P-Selectin; P-selectin ligand protein; Participant; Patients; Pattern; Pharmacogenetics; Phenotype; Plasma; Platelet aggregation; Predisposition; Prevention; Proteins; Pulmonary Inflammation; Risk; SELP gene; Sampling; Selectins; Sepsis; Severities; Signal Pathway; Stratification; TLR4 gene; Therapeutic; Therapeutic Clinical Trial; Thrombosis; Transferase; Validation; Variant; anakinra; biomarker panel; clinically relevant; design; extracellular; genetic variant; health disparity; improved; innovation; insight; lung injury; member; mortality; mortality risk; multiorgan injury; neutralizing monoclonal antibodies; novel; novel marker; novel therapeutics; patient stratification; pharmacologic; point of care; pre-clinical; predictive marker; predictive test; radiological imaging; systemic inflammatory response; therapeutic target; tool

PROJECT SUMMARY: The COVID-19 pandemic has dramatically highlighted serious unmet needs of ARDS including 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. Predictive biomarkers, either protein- or genomic-based, that identify specific ARDS sub-phenotypes and likely responders to specific ARDS therapeutics, could significantly influence effective clinical trial designs to assess novel therapeutics and therefore benefit the outcomes of ARDS trials. Our group has long championed the utility of genomic-intensive approaches to identify multiple novel ARDS therapeutic targets. We previously identified eNAMPT (extracellular nicotinamide phosphoribosyl transferase) as a novel ARDS therapeutic target/gene which serves as a damage-associated molecular pattern protein (DAMP) and ligand for Toll-like receptor 4 (TLR4). NAMPT SNPs predict ARDS severity and eNAMPT amplifies dysregulated lung/systemic inflammatory responses that contribute to multi- organ injury/failure. We demonstrated the utility of a humanized eNAMPT-neutralizing mAb as a therapeutic strategy in ARDS and other inflammatory conditions. Plasma eNAMPT, along with IL-6, IL-8, IL-1RA, MIF, and Ang-2, was highly predictive of 28-day ARDS mortality. We also identified variants in selectin P ligand gene (SELPLG) encoding P-selectin glycoprotein ligand 1 (PSGL1), and P-selectin gene (SELP) as associated with increased susceptibility to ARDS in Blacks. PSGL1/P-selectin interactions are critical to lung inflammation via leukocyte trafficking, platelet aggregation, and thrombosis. Plasma PSGL1 and P-selectin levels are significantly elevated in sepsis, ARDS, and COVID-19 pneumonia patients and PSGL1 inhibition (mAb, TSGL-Ig) significantly attenuates preclinical lung injury in ARDS. This R-21 application will utilize over 900 plasma samples and genotyping results available from the NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Reevaluation of systemic Early neuromuscular blockade (ROSE) study (see NHLBI BioLINCC letter). We will validate two highly novel stratification tools to improve patient stratification in the design of future ARDS clinical trials targeting eNAMPT/TLR4 and PSGL1/P-Selectin interactions. Specific Aim (SA) #1 will develop a genotype-based biomarker assay combining: i) carefully selected SELPLG/SELP variants with plasma PSGL1/P-selectin levels, and ii) NAMPT variants with plasma eNAMPT levels. These genotypes will identify ARDS subjects as candidates for future clinical trials targeting PSGL-1/P-selectin interactions and the eNAMPT/TLR4 signaling pathway. SA #2 will validate the predictive capacity of a seven-biomarker panel (eNAMPT, IL-6, IL-8, IL-1RA, PSGL-1, IL-1β, Ang-2) for ARDS mortality. Successful completion of this highly innovative R21 grant will generate a novel ‘point of care’ pharmacogenetic enrichment tools to be leveraged in designing human ARDS clinical trials targeting PSGL1/P-selectin and eNAMPT/TLR4 interactions.

项目概要： COVID-19 大流行极大地凸显了 ARDS 严重未得到满足的需求，包括缺乏 FDA 批准的有效药物干预措施可解决 ARDS 死亡率。 异质性、炎症失调的复杂性以及预测生物标志物的缺乏都影响了 导致 ARDS 治疗临床试验失败的原因是基于蛋白质或基因组的预测生物标志物。 识别特定的 ARDS 亚表型和对特定 ARDS 治疗的可能反应者，可以 显着影响有效的临床试验设计以评估新疗法，从而使 我们的团队长期以来一直倡导使用基因组密集型方法来识别 ARDS 试验的结果。 我们之前发现了多个新的 ARDS 治疗靶点。 磷酸核糖基转移酶）作为一种新的 ARDS 治疗靶点/基因，作为损伤相关的 分子模式蛋白 (DAMP) 和 Toll 样受体 4 (TLR4) 的配体可预测 ARDS。 严重程度和 eNAMPT 会放大失调的肺部/全身炎症反应，从而导致多种 我们展示了人源化 eNAMPT 中和单克隆抗体作为治疗药物的效用。 ARDS 和其他炎症性疾病的血浆 eNAMPT 以及 IL-6、IL-8、IL-1RA、MIF 和 Ang-2 高度预测 28 天 ARDS 死亡率 我们还鉴定了选择蛋白 P 配体基因的变异。 (SELPLG) 编码 P-选择素糖蛋白配体 1 (PSGL1)，以及与相关的 P-选择素基因 (SELP) PSGL1/P-选择素相互作用对黑人 ARDS 的易感性增加对肺部炎症至关重要。 白细胞运输、血小板聚集和血栓形成显着。 在脓毒症、ARDS 和 COVID-19 肺炎患者中升高，PSGL1 抑制（mAb、TSGL-Ig）显着 减轻 ARDS 的临床前肺损伤。该 R-21 应用将利用 900 多个血浆样本和 基因分型结果可从 NHLBI 急性肺损伤预防和早期治疗 (PETAL) 获得 系统性早期神经肌肉阻滞 (ROSE) 研究的网络重新评估（参见 NHLBI BioLINCC 信件）。 我们将验证两种高度新颖的分层工具，以改善未来 ARDS 设计中的患者分层 针对 eNAMPT/TLR4 和 PSGL1/P-Selectin 相互作用的临床试验将开发一种特定目标 (SA) #1。 基于基因型的生物标志物测定结合： i) 精心挑选的 SELPLG/SELP 变体与血浆 PSGL1/P-选择素水平，和 ii) NAMPT 变异体与血浆 eNAMPT 水平将识别这些基因型。 ARDS 受试者作为未来针对 PSGL-1/P-选择素相互作用的临床试验的候选者 eNAMPT/TLR4 信号通路 SA #2 将验证七种生物标志物组的预测能力。 （eNAMPT、IL-6、IL-8、IL-1RA、PSGL-1、IL-1β、Ang-2）成功完成了这一高度的 ARDS 死亡率。 创新的 R21 资助将产生一种可供利用的新型“护理点”药物遗传学富集工具 设计针对 PSGL1/P-选择素和 eNAMPT/TLR4 相互作用的人类 ARDS 临床试验。