Hyperpolarized xenon functional MRI of human lung microstructure

描述(申请人提供)：慢性阻塞性肺疾病(COPD)，包括肺气肿和慢性支气管炎，是美国第四大死亡原因，每年有12万人死亡。它是死亡率上升的唯一主要死因，1980至2000年间死亡率上升了67%。虽然有1400万美国人被诊断出患有慢性阻塞性肺疾病，但估计还有2000万患者没有得到诊断。慢性阻塞性肺病每年造成的经济负担估计为350亿美元。FDA批准的功能磁共振成像(MRI)试剂将为疾病诊断和表型鉴定提供更高的特异性，将有助于向个人提供更个性化的药物，并将为进行药物试验的制药公司提供更大的统计学意义。与CT不同，MRI不使用电离辐射，因此可以重复使用。超极化气体磁共振成像在评估肺功能微结构和与肺气肿相关的微结构变化方面提供了精细的细节。弥散加权成像产生表观弥散系数(ADC)的区域图，该图对肺泡间隔是否完整敏感。虽然使用129Xe和3He都成功地进行了ADC测量，但只有氙气可以直接检测到这些气体交换膜的存在。我们的团队是第一个在人类身上展示氙气磁化传递对比(XTC)的小组。通过反复操纵溶解在组织中的129Xe磁化强度，并允许这些自旋改变气相的极化，XTC对局部气体交换表面积提供了无与伦比的敏感性。此外，由于129Xe在自然界中含量丰富，只有氙气为广泛的肺微结构临床成像提供了一种商业上可行的策略。XMERE已经获得了FDA对人体试验的批准，完成了第一阶段的试验，并进入了第二阶段，并致力于完成监管过程，并确保其标志性成像剂MagniXene}的新药地位。在此第二阶段计划中，我们将在定量精度、应用程序通用性和诊断相关性方面扩展我们的ADC和XTC协议。我们对第一阶段已经实施的两项协议改进的研究将确保高度的重复性和内部交叉检查。所有协议都将针对当前的2D投影和1D直方图以及新的2D切片和3D渲染进行优化。ADC研究将扩展到包括刺激回声研究，这可能提供对侧支通气量变化的敏感性，提高对早期肺气肿的诊断。XTC研究将扩展到比较短和长的气体交换时间，以及对隔壁增厚和血流的敏感性。将进行逐个体素的可重复性研究。参数将在健康志愿者和轻中度肺部疾病患者身上进行优化。这项研究是FDA第二阶段试验计划的第一部分，将标准化肺气肿的生物标志物，使MagniXene作为一种安全、有效和商业上可行的肺部疾病显像剂进行FDA第二阶段的大规模临床试验。

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD), including emphysema and chronic bronchitis, is the fourth leading cause of death in the US, accounting for 120,000 fatalities annually. It is the only leading cause of death with rising mortality, with death rate increasing 67% between 1980 and 2000. While 14 million Americans are diagnosed with COPD, an estimated 20 million additional sufferers remain undiagnosed. The yearly economic burden of COPD is estimated at 35 billion US$. An FDA-approved functional magnetic resonance imaging (MRI) agent would provide greater specificity for disease diagnosis and phenotyping, would assist in delivering more personalized medicine to individuals, and would offer greater statistical significance to pharma companies conducting drug trials. Unlike CT, MRI uses no ionizing radiation so it can be used repeatedly. Hyperpolarized gas MRI offers exquisite detail in assessments of lung functional microstructure and microstructural changes associated with emphysema. Diffusion-weighted imaging yields regional maps of Apparent Diffusion Coefficient (ADC) which is sensitive to whether alveolar septa are intact. While ADC measurements have been demonstrated successfully using both 129Xe and 3He, only xenon can directly sense the presence of these gas exchange membranes. Our group is the first to demonstrate Xenon magnetization Transfer Contrast (XTC) in humans. By repeatedly manipulating the 129Xe magnetization dissolved in the tissues and allowing those spins to modify the polarization of the gas phase, XTC offers unparalleled sensitivity to local gas exchange surface area. Furthermore, since 129Xe is abundant in nature only xenon offers a commercially viable strategy for widespread clinical imaging of lung microstructure. Xemed has secured FDA approval for human subject testing, completed Phase 1 trials and advanced to Phase 2, and is committed to completing the regulatory process and securing New Drug status for its signature imaging agent MagniXene}. In this Phase 2 proposal we will extend our ADC and XTC protocols in quantitative precision, application versatility, and diagnostic relevance. Our investigation of two protocol refinements added to the two we already implemented in Phase 1 will assure high reproducibility and internal crosschecks. All protocols will be optimized for the present 2D projections and 1D histograms, as well as for new 2D slices and 3D renderings. ADC studies will be extended to include stimulated echo studies, which may provide sensitivity to changes in collateral ventilation, enhancing diagnosis of early emphysema. XTC studies will be extended to compare short and long gas exchange times, with sensitivity to septal wall thickening and blood flow. Voxel-by-voxel reproducibility studies will be performed. Parameters will be optimized on healthy volunteers and patients with mild to moderate lung disease. This study, the first component of our Phase 2 FDA trial program, will standardize biomarkers for emphysema, leading to a large-scale Phase 2 FDA clinical trial of MagniXene} as a safe, effective, and commercially viable imaging agent for pulmonary disease.