Project 3. Mechanisms of benefit of biologic agents for patients with aspirin-exacerbated respiratory disease (AERD)

项目3.生物制剂对阿司匹林急性呼吸道疾病（AERD）患者的获益机制

• 批准号: 10626855
• 负责人: Tanya Maria Laidlaw
• 金额: $ 37.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626855
• 关键词: Address; Adult; Affect; Anosmia; Asthma; Automobile Driving; Biological; Biological Products; Biological Response Modifier Therapy; Biology; Cell Aging; Cells; Chronic; Clinical; Clinical effectiveness; Controlled Clinical Trials; Data; Diagnosis; Dinoprostone; Disease; Double-Blind Method; Effector Cell; Epithelial Cells; FDA approved; Functional disorder; Growth; Histology; Impairment; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interruption; Intervention Studies; Learning; Link; Mediator; Nasal Polyps; Nose; Outcome Measure; Pain; Pathway interactions; Patient Agents; Patients; Pharmaceutical Preparations; Placebo Control; Play; Polyps; Production; Prostaglandin Production; Recurrence; Role; Severities; Signal Transduction; Sinus; Smell Perception; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Tumorigenicity; Work; airway inflammation; antagonist; aspirin-exacerbated respiratory disease; cellular targeting; chronic rhinosinusitis; clinical efficacy; cohort; comparative efficacy; cysteinyl-leukotriene; cytokine; cytokine therapy; effective therapy; experience; improved; inhibitor; innovation; mast cell; mastocytosis; novel; polyposis; respiratory; therapeutic target; therapy outcome; trial design

PROJECT SUMMARY/ABSTRACT Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory syndrome that affects 14% of adults with severe asthma, and 30% of adults with asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Patients with AERD develop recurrent nasal polyps that cause nasal blockage, sinus pain, and complete loss of sense of smell. Neither the initial cause nor the driver of ongoing inflammation and polyp regrowth are known, and there are few effective therapies. Newly developed biologic anti-type 2 cytokine therapies are a significant treatment advance, but the roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with asthma, CRSwNP, and AERD are not known. Our preliminary data show that AERD pathophysiology involves persistently abnormal functions of both mast cells and epithelial cells within the nasal polyp tissue, which contributes to disease persistence, recurrence and severity. The dysregulation of these cells is tightly linked and potentially regulated by IL-4Rα and IL-33 signaling. This Project will determine the cell-specific roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with AERD and nasal polyposis. Using a double-blind, placebo-controlled parallel-design trial of dupilumab, a potent IL-4Rα antagonist, and REGN3500, a potent IL-33 inhibitor, we will test the central hypotheses that (1) the rapid onset of clinical improvement provided by IL-4Rα inhibition with dupilumab in AERD is due largely to the drug’s direct effects on both MCs and EpCs; and (2) REGN3500 will rapidly and directly suppress MC activation, but will not effect EpCs until it inhibits IL-13 production, and therefore will have a more delayed onset for full clinical effectiveness. Aim 1 will determin the efficacy of dupilumab and REGN3500 as treatments for AERD. Aim 2 will determine the relevance of IL-4Rα and IL-33/ST2 signaling on on mast cell activation, epithelial cell dysfunction, and the respiratory inflammation in AERD. To address our hypotheses, we propose the following Aims: Aim 1. Compare the clinical efficacy of anti-IL-4α (dupilumab) and anti-IL-33 (REGN3500) as treatments for nasal polyps in AERD in a double-blind, placebo-controlled clinical trial. Aim 2. Define the mechanism(s) of anti-IL-4Rα and anti-IL-33-induced therapeutic benefit in AERD by linking early and later changes in mediator and effector cell readouts to clinical efficacy.

项目概要/摘要 阿司匹林加重的呼吸道疾病 (AERD) 是一种慢性炎症综合征，影响 14% 的人 患有严重哮喘的成人，以及 30% 患有哮喘和慢性鼻窦炎并伴有鼻息肉的成人 （CRSwNP）。 AERD 患者会出现复发性鼻息肉，导致鼻塞、鼻窦疼痛和 嗅觉完全丧失。既不是持续炎症和息肉的最初原因，也不是驱动因素 再生是已知的，并且几乎没有有效的治疗方法。新开发的生物抗2型细胞因子 疗法是一项重大的治疗进展，但 IL-4Rα 和 IL-33/ST2 信号传导在驱动 困扰哮喘、CRSwNP 和 AERD 患者的慢性呼吸道炎症尚不清楚。 我们的初步数据表明，AERD 病理生理学涉及两者的持续异常功能 鼻息肉组织内的肥大细胞和上皮细胞，这有助于疾病的持续存在， 复发和严重程度。这些细胞的失调与 IL-4Rα 密切相关并可能受到 IL-4Rα 的调节 和 IL-33 信号传导。该项目将确定 IL-4Rα 和 IL-33/ST2 信号传导的细胞特异性作用 导致慢性呼吸道炎症困扰 AERD 和鼻息肉病患者。使用 dupilumab（一种有效的 IL-4Rα 拮抗剂）的双盲、安慰剂对照平行设计试验，以及 REGN3500 是一种有效的 IL-33 抑制剂，我们将测试以下中心假设：(1) 临床快速起效 Dupilumab 抑制 IL-4Rα 对 AERD 的改善主要归因于该药物的直接作用 在 MC 和 EpC 上； (2) REGN3500会快速直接抑制MC激活，但不会影响 EpCs 直到它抑制 IL-13 的产生，因此全面临床的起效将更加延迟 效力。目标 1 将确定 dupilumab 和 REGN3500 作为 AERD 治疗的疗效。目标2 将确定 IL-4Rα 和 IL-33/ST2 信号传导对肥大细胞活化、上皮细胞的相关性 AERD 中的功能障碍和呼吸道炎症。为了解决我们的假设，我们提出以下建议 目标： 目标 1. 比较抗 IL-4α (dupilumab) 和抗 IL-33 (REGN3500) 治疗的临床疗效 鼻息肉治疗 AERD 的双盲、安慰剂对照临床试验。 目标 2. 通过联系确定抗 IL-4Rα 和抗 IL-33 在 AERD 中诱导的治疗益处的机制 介质和效应细胞读数的早期和后期变化对临床疗效的影响。