UTE MRI to monitor CF lung disease and response to CFTR modulation in young children

 描述（由申请人提供）：囊性纤维化（CF）是一种进行性全身性疾病，在美国影响估计30，000名儿童和成人（全球70，000名）。它是由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起的，最终导致肺气道功能障碍。病理变化开始为粘液淤滞、炎症、感染和气道重塑，并导致进行性空气滞留、通气不均匀性和支气管扩张。CF管理的一个主要差距是在临床护理和治疗反应中监测早期和局部肺部疾病的能力。因此，在临床症状出现之前，评估伴随局部和整体通气异常的结构变化对于我们理解年轻CF人群中它们之间的关系至关重要。靶向囊性纤维化最常见病因的CFTR调节剂（F508 del CFTR，在> 85%的CF患者中发现）最近在F508 del纯合子儿科患者中证明了疗效。目前迫切需要监测CFTR调节剂在儿童中疗效的工具，因为这些新型疗法最近在2015年获得FDA批准，可用于≥ 12岁的患者。现有的肺功能检测通过肺功能测定是不敏感的局部肺部疾病，几乎是不可能使用的幼儿;支气管镜检查是侵入性的，不敏感的局部疾病。虽然胸部CT能够检测局部肺部异常，但辐射暴露限制了其长期用于纵向（例如，年度）评估，并提供有限的功能信息。肺磁共振成像（MRI）的最新突破为推进该技术用于监测年轻患者和轻度疾病患者的CF肺病进展和治疗反应奠定了基础。超短回波时间（UTE）MRI提供了可与标准CT成像相媲美的高分辨率结构数据，我们研究团队的最新工作表明，肺部UTE MRI可以识别年轻CF患者先前通过CT识别的每种结构异常。在我们的建议中，首要的假设是MRI可以作为一种敏感的工具，纵向监测CF肺部疾病的进展和CFTR调节剂治疗的CF儿童，没有暴露于电离辐射。我们将通过验证6-12岁的UTE MRI来检验这一假设。通过与CT进行比较（目的1），纵向量化相同患者的疾病轨迹以及一半符合药物资格的患者对CFTR调节剂治疗的反应（目的2），以及通过敏感的局部通气异质性测量（肺清除指数和超极化129 MRI）检查局部结构-功能关系（目的3），对儿童CF患者进行研究。

 DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a progressive, systemic disease affecting an estimated 30,000 children and adults in the United States (70,000 worldwide). It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which ultimately lead to lung-airway dysfunction. Pathological changes begin as mucus stasis, inflammation, infection, and airway remodeling and result in progressive air trapping, ventilation inhomogeneity, and bronchiectasis. A major gap in CF management is the capacity to monitor early and regional lung disease, both in clinical care and in response to therapies. Thus, evaluating structural changes concomitant with regional and global ventilation abnormalities is paramount to our understanding of their relationships in the young CF population, prior to the onset of clinical symptoms. CFTR modulators that target the most common cause of cystic fibrosis (F508del CFTR, found in > 85% of CF patients) have recently demonstrated efficacy in F508del homozygous, pediatric patients. Tools to monitor CFTR modulator efficacy in children are an urgent need, as these novel therapies were recently granted FDA approval in 2015 for patients ≥ 12 years of age. Existing pulmonary function testing via spirometry is insensitive to regional lung disease and is nearly impossible to use in young children; bronchoscopy is invasive and insensitive to regional disease. While chest CT is capable of detecting regional lung abnormalities, radiation exposure limits its long-term use for longitudinal (e.g., yearly) evaluation and provides limited functional information. Recent breakthroughs in pulmonary magnetic resonance imaging (MRI) set the foundation to advance this technology for monitoring CF lung disease progression and response to therapy in young patients, and patients with mild disease. Ultrashort echo time (UTE) MRI provides high resolution structural data that rivals standard CT imaging, and recent work from our research team demonstrates that pulmonary UTE MRI can identify each of the structural abnormalities previously identified by CT in young CF patients. The overarching hypothesis in our proposal is that MRI can serve as a sensitive tool to longitudinally monitor CF lung disease progression and response to CFTR modulator therapy in children with CF, without exposure to ionizing radiation. We will test this hypothesis by validating UTE MRI in 6-12 y.o. pediatric CF patients by comparison to CT (Aim 1), by longitudinally quantifying disease trajectory in those same patients and also response to CFTR modulator therapy in the half who will be drug-eligible (Aim 2), and by examining regional structure-function relationships via sensitive measures of regional ventilation heterogeneity: lung clearance index and hyperpolarized 129Xe MRI (Aim 3).