Using MRI To Visualize Regional Therapy Response In Idiopathic Pulmonary Fibrosis

项目摘要/摘要 特发性肺纤维化(IPF)的患病率在过去10年中翻了一番，达到约300万患者 全世界。它的预后比许多癌症都要差，如果不治疗，中位生存期为3-5年。 虽然IPF无法治愈，但新推出的药物可以将肺功能下降的速度减缓~50%。 安慰剂，尽管每年花费10万美元，对个别患者的疗效尚不清楚。今天，IPF 临床护理和研究因缺乏可靠地评估其异质性地区的工具而受阻 功能损害检测疾病，并提供积极治疗反应的可靠指标。对这件事 最后，我们开发了超极化(HP)129Xe磁共振成像，并展示了它可以提供快速、非侵入性的3D 对吸入气体在空气空间中的分布及其在间质(屏障)中的吸收进行功能评估 组织)，并转移到毛细血管红细胞(RBC)。我们已经证明了它对微米的敏感性- 间质屏障的鳞片增厚，这为治疗提供了一个敏感的早期标志 回应。这导致了对更广泛传播以及统一获取和量化的要求 使可重复性最大化的协议。我们的长期目标是广泛传播全面而快速的 (15分钟)，无创，健壮，敏感的纤维性肺部疾病的MRI检查。我们带来了先进的HP 129Xe MR采集和分析技术与三位先驱胸部MRI专业知识的记录 开发此应用程序的中心。此次更新的目标是优化对变化的敏感度 疾病，最大限度地提高重复性，协调采集和分析，并建立其生理和临床 释义。我们的中心假设是，这些方法将使我们能够确信地检测到可治疗的 并在启动后3个月内观察治疗反应。建议进行这项研究的理由 是由行业和学术合作伙伴的强烈兴趣以及FDA即将批准的129Xe推动的 通风核磁共振，将加快采用。因此，拟议的研究与美国国立卫生研究院的 通过发展和加快生物医药技术的应用来改善健康。我们的方法是 基于三个具体目标：1)建立跨MRI平台的129Xe指标的最佳重复性；2) 建立统一的定量分析，以及3)部署和验证确定活动性纤维化的框架 和治疗反应。完成这些目标将1)使标准协议在扫描仪中可用 平台，2)建立最大限度地提高可重复性的标准，以及3)提供所需的工具和框架 将129Xe磁共振纳入进展性纤维化的多中心试验，并最终用于临床护理。建议数 方法是创新的，因为它建立在一种全新的方法之上，以探索 肺泡-毛细血管界面。它具有重要意义，因为它将使人们能够广泛采用方法来推进 我们对纤维化肺疾病的了解，加快了新疗法的测试，并改善了患者护理。

Project Summary/Abstract The prevalence of Idiopathic pulmonary fibrosis (IPF) has doubled in the past 10 years to ~3 million patients worldwide. It has a prognosis worse than for many cancers, and, if untreated, has a median survival of 3–5 years. While IPF has no cure, newly available medications can slow the rate lung function decline by ~50% relative to placebo, albeit at a cost of $100,000 per year, and with unknown efficacy in individual patients. Today, IPF clinical care and research are stymied by a lack of tools that can reliably assess its heterogeneous regional functional impairment to detect disease and provide robust indicators of positive therapeutic response. To this end, we have developed hyperpolarized (HP) 129Xe MRI and shown it to provide rapid, non-invasive, 3D functional assessment of inhaled gas distribution in the airspaces, as well as its uptake in the interstitium (barrier tissues) and transfer to the capillary red blood cells (RBCs). We have demonstrated its sensitivity to micron- scale thickening of the interstitial barrier and that this provides a sensitive and early marker of therapeutic response. This has led to demands for wider dissemination and harmonized acquisition and quantification protocols that maximize repeatability. Our long-term goal is to broadly disseminate a comprehensive, yet rapid (15 min), non-invasive, robust, and sensitive MRI exam for fibrotic lung disease. We bring advanced HP 129Xe MR acquisition and analysis techniques and a track-record of thoracic MRI expertise from three pioneering centers that have developed this application. The objective of this renewal is to optimize sensitivity to changing disease, maximize repeatability, harmonize acquisition and analysis and establish its physiological and clinical interpretation. Our central hypothesis is that this these methods will enable confident detection of treatable disease and visualize therapeutic response within 3 months of initiation. The rationale for the proposed research is driven by strong interest from both industry and academic partners, and impending FDA approval for 129Xe ventilation MRI that will accelerate adoption. Thus, the proposed research is relevant to the NIH Mission of improving health by developing and accelerating the application of biomedical technologies. Our approach is based on three Specific Aims: 1) Establish optimal repeatability of 129Xe metrics across MRI platforms, 2) Establish harmonized quantitative analysis, and 3) Deploy and validate a framework to identify active fibrosis and therapy response. Completion of these aims will 1) make available standardized protocols across scanner platforms, 2) establish standards that maximize repeatability, and 3) provide the tools and framework needed to incorporate 129Xe MRI into multi-center trials for progressive fibrosis and ultimately, clinical care. The proposed approach is innovative because it is built on a fundamentally new approach to probe the functioning of the alveolar-capillary interface. It is significant because it will enable widespread adoption of methods to advance our understanding of fibrotic lung disease, accelerate testing of novel therapies, and improve patient care.