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)是一种进行性系统性疾病，在美国估计有30,000名儿童和成人受到影响(全球70,000人)。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-呼吸道功能障碍。病理改变开始于粘液淤积、炎症、感染和呼吸道重塑，并导致进行性空气滞留、呼吸不均匀和支气管扩张。CF管理中的一个主要差距是在临床护理和治疗反应中监测早期和区域性肺部疾病的能力。因此，在临床症状出现之前，评估伴随局部和整体换气异常的结构性改变对于我们了解年轻CF人群中它们之间的关系是至关重要的。针对囊性纤维化最常见原因的CFTR调节剂(F508del CFTR，在85%的CF患者中发现)最近在F508del纯合子的儿科患者中证明有效。迫切需要监测cftr调节剂在儿童中的疗效的工具，因为这些新疗法最近于2015年获得食品和药物管理局的批准，适用于12岁的患者≥。现有的通过肺活量测定法进行的肺功能测试对区域性肺部疾病不敏感，几乎不可能在幼儿中使用；支气管镜检查是侵入性的，对区域性疾病不敏感。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，并且提供的功能信息有限。最近在肺磁共振成像(MRI)方面的突破为推动这项技术的发展奠定了基础，该技术用于监测年轻患者和轻度疾病患者的CF肺部疾病进展和治疗反应。超短回波时间(UTE)磁共振成像提供了与标准CT成像相媲美的高分辨率结构数据，我们研究团队最近的工作表明，肺UTE MRI可以识别年轻CF患者中CT以前发现的每一种结构异常。我们建议的最重要的假设是，MRI可以作为一种敏感的工具，在不暴露于电离辐射的情况下，纵向监测患有CF的儿童的CF肺部疾病进展和对CFTR调节剂治疗的反应。我们将在6-12年内通过验证UTE MRI来验证这一假设。通过与CT(目标1)进行比较，通过纵向量化这些患者的疾病轨迹以及将获得药物资格的一半患者对CFTR调节剂治疗的反应(目标2)，以及通过区域通风异质性的敏感指标：肺清除指数和超极化129Xe MRI(目标3)来检查区域结构-功能关系。

 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).