Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping

摘要 哮喘影响全球超过3亿人。据估计， 2013年美国哮喘的诊断和管理。不受控制的哮喘与加倍的 直接成本;据估计，20%的哮喘受试者贡献了80%的经济成本， 哮喘对于严重哮喘，有多种新的FDA批准的生物疗法，但它们仍然非常昂贵 有相当一部分人没有反应。目前的生物标志物可能无法可靠地区分 应答者和非应答者;预期应答者中约40%继续发生急性加重，约40% 那些没有反应的人都没有症状了。在这个建议中，我们将使用新的基因组学方法， 使用治疗诱导的表型在哮喘严重程度范围内评估和预测反应， 内型我们假设，使用临床指标，“组学”方法， 新的系统生物学方法将产生更精确的治疗反应生物标志物， 疾病异质性，并发现与治疗中度至重度 哮喘为了解决这一假设，我们指定了三个具体的目标，围绕着以下组合： 一个经过充分表征的人内诱发表型临床队列，包括同时患有2型（即 根据目前的生物标志物预期应答的患者）和非2型中度至重度哮喘患者，对抗IL 5 （贝那利珠单抗）和抗IL 4/IL 13（dupilumab），包括单细胞和原液 每种生物干预措施中痰液和血液的RNA测序。第一个目标是 鉴定并随后验证预测对每种治疗反应的药物基因组学转录物，从而 产生对哮喘生物制剂的反应的临床相关生物标志物。我们的第二个目标是利用 生物干预作为特定途径的免疫调节剂，作为“人类敲低模型”， 在单细胞水平上对生物疗法的潜在机制反应。最终目标将 通过表征影响临床哮喘的基因组信号，提供对队列的新见解 亚型，并通过分子内型的鉴定，这将与传统的临床 亚型，并评估其对生物制剂的反应。对每个目标的分析包括传统的 统计模型以及新的系统医学和网络生物学方法。我们的优势 研究包括将独特的纵向临床诱发表型队列与最先进的基因组学融合 分析。本研究的成功完成将促进对生物制剂的严重哮喘反应的理解 到前所未有的水平，提供了新的治疗生物标志物，导致直接的临床应用，并详细说明 严重哮喘的细胞和基因通路机制以前未知。

Abstract Asthma affects over 300 million individuals worldwide. An estimated $81.9 billion dollars were spent on the diagnosis and management of asthma in the U.S. in 2013. Uncontrolled asthma is associated with a doubling of direct costs; it has been estimated that 20% of the subjects with asthma contribute 80% of the economic costs of asthma. For severe asthma, multiple new FDA approved biologic therapies exist, but they remain very expensive and there are a significant proportion of nonresponders. Current biomarkers may not distinguish reliably between responders and non-responders; ~40% of those expected to respond continue to have exacerbations and ~40% of those not expected to respond become symptom free. In this proposal, we will use novel genomics approaches to assess and predict responses using therapy-induced phenotypes across a spectrum of asthma severity and endotypes. We hypothesize that comprehensive characterization using clinical metrics, ‘omics’ approaches, and novel systems biology approaches will generate more precise treatment response biomarkers, further define disease heterogeneity, and uncover novel biologic mechanisms as related to the therapy of moderate to severe asthma. To address this hypothesis, we have specified three specific aims, centered around the combination of a well-characterized, within-person evoked phenotype clinical cohort, including subjects with both type 2 (i.e. those expected to respond based on current biomarkers) and non-type 2 moderate to severe asthma, to anti-IL5 (benralizumab) and anti-IL4/IL13 (dupilumab) with deep genomic interrogation, including single cell and bulk RNA sequencing in both sputum and blood across each of the biologic interventions. The first aim will be to identify, and subsequently validate, pharmacogenomic transcripts that predict response to each therapy, thereby yielding clinically relevant biomarkers for response to asthma biologics. Our second aim takes advantage of the biologic interventions as immunomodulators of specific pathways serving as “human knockdown models” to elicit the underlying mechanistic response at the level of the single cell to the biologic therapies. The final aim will provide novel insights into cohort via the characterization of genomic signals that influence clinical asthma subtypes and via the identification of molecular endotypes, which will be compared to the tradtional clinical subtypes and evaluated for their response to the biologics. Analyses for each aim with include both traditional statistical models as well as novel systems medicine and network biology approaches. The strengths of our study include a melding a unique longitudinal clinical evoked phenotype cohort with state of the art genomics analyses. Successful completion of this study will drive understanding of severe asthma response to biologics to an unprecendented level, provide novel therapeutic biomarkers leading to direct clinical application, and detail previously unknown cellular and genomic pathway mechanisms underlying severe asthma.