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: 10456246
• 负责人: Tanya Maria Laidlaw
• 金额: $ 43.16万
• 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/10456246
• 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; Congestive; Controlled Clinical Trials; Data; Dinoprostone; Disease; Double-Blind Method; Effector Cell; Epithelial Cells; FDA approved; Functional disorder; Histology; Impairment; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interruption; Intervention Studies; Learning; Link; Mediator of activation protein; Nasal Polyps; Nose; Outcome Measure; Pain; Pathway interactions; Patient Agents; Patients; Pharmaceutical Preparations; Placebo Control; Play; Polyps; Problem Solving; 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; base; cellular targeting; chronic rhinosinusitis; clinical efficacy; cohort; comparative efficacy; cysteinyl-leukotriene; cytokine; cytokine therapy; effective therapy; experience; 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.

项目摘要/摘要 阿司匹林呼吸道疾病（AERD）是一种慢性炎症综合症，影响14％ 患有严重哮喘的成年人，有30％的成年人患有哮喘和慢性鼻鼻炎患有鼻多息护素 （CRSWNP）。 AERD患者会出现复发性鼻息肉，导致鼻部阻塞，鼻窦疼痛和 完全失去嗅觉。最初的原因也不是持续的炎症和息肉的驱动力 再生是已知的，几乎没有有效的疗法。新开发的生物抗型2细胞因子 疗法是一个重大的治疗疗法，但是IL-4Rα和IL-33/ST2信号在驱动驱动器中的作用 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，AIRD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，这有助于疾病持续性， 复发和严重性。这些细胞的失调紧密连接，并可能由IL-4Rα调节 和IL-33信号传导。该项目将确定IL-4Rα和IL-33/ST2信号在细胞特异性的作用 驱动慢性呼吸道感染，困扰着AERD和鼻多息护物的患者。使用 双盲，安慰剂对照的平行设计试验，潜在的IL-4Rα拮抗剂和 Regn3500是一种潜在的IL-33抑制剂，我们将测试（1）临床快速发作的中心假设 AERD中用Dupilumab抑制IL-4Rα提供的改进主要是由于该药物的直接作用 在MC和EPC上； （2）regn3500将迅速并直接抑制MC激活，但不会影响 EPC直到它抑制IL-13的产生，因此将更延迟发作以进行全临床 效力。 AIM 1将确定Dupilumab和Regn3500作为AERD处理的有效性。目标2 将确定肥大细胞激活上IL-4Rα和IL-33/ST2信号传导的相关性 功能障碍和AERD中的呼吸道注射。为了解决我们的假设，我们提出以下内容 目标： AIM 1。将抗IL-4α（Dupilumab）和抗IL-33（Regn3500）的临床效率比较 在双盲，安慰剂对照的临床试验中，AERD中的鼻息肉。 AIM 2。通过连接通过链接到AERD中抗IL-4Rα和抗IL-33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为临床有效性。