Molecular imaging of angiogenic activity in pulmonary arterial hypertension

 描述（由申请人提供）： 肺动脉高压（PAH）是一种肺血管阻力升高的疾病，其特征是肺循环阻力决定血管的进行性增厚和闭塞。尽管有目前的治疗，PAH诊断后的5年生存率仍约为50%，死亡率是疾病进展和右心衰竭的结果。延迟诊断、缺乏更直接的疾病活动性生物标志物以及缺乏可以阻止或逆转肺血管重塑的治疗都是PAH结局改善的障碍。一种直接监测肺血管疾病活动的灵敏、非侵入性成像检查可以帮助加快诊断并确定有效的干预措施。该提议将验证新型正电子发射断层扫描（PET）分子成像模式的效用，使用89 Zr-贝伐单抗检测受PH影响的血管中的病理性VEGF活性。初步数据表明，使用89 Zr-贝伐单抗的PET成像检测实验性PAH中肺血管系统的远端循环中增强的VEGF活性，并且具有识别人类PAH中重塑的活动性病变的潜力。这些研究将直接测试PET 89 Zr-贝伐珠单抗成像是否可以在发生显著血管损失和血流动力学显著PAH之前检测早期疾病，预测疾病的严重程度和进展，并反映获批血管扩张剂和新型治疗干预阻断肺循环中血管生成重塑活性的能力。将采用离体灌注方法，使用受PAH影响的活体、移植人肺进行验证研究，以提高这些结果可翻译性的置信度。这种方法的验证将构成我们评估临床医生通常无法获得的血管床中正在进行的重塑的能力的突破，以允许对疾病严重程度和风险进行客观分层，基于疾病活动度定制药物治疗，并可能识别通过全新机制起作用的治疗以阻止或逆转疾病进展。(End摘要）

 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive thickening and obliteration of resistance-determining vessels of the pulmonary circulation. Despite current therapies, survival following the diagnosis of PAH remains approximately 50% at 5 years, with mortality a result of disease progression and right heart failure. Delayed diagnosis, the lack of more direct biomarkers of disease activity, and the lack of treatments that can arrest or reverse pulmonary vascular remodeling are all barriers to improved outcomes in PAH. A sensitive, non-invasive imaging test that directly monitors pulmonary vascular disease activity could help expedite diagnosis and identify effective interventions. This proposal will validate the utility of a novel positron emission tomography (PET) molecular imaging modality, using 89Zr-bevacizumab to detect pathologic VEGF activity in the vessels affected by PH. Preliminary data demonstrates that PET imaging using 89Zr- bevacizumab detects enhanced VEGF activity in the distal circulation of the pulmonary vasculature in experimental PAH, and has the potential to recognize active lesions of remodeling in human PAH. These studies will directly test whether or not PET 89Zr- bevacizumab imaging can detect early disease, prior to the development of significant vessel loss and hemodynamically significant PAH, predict the severity and progression of disease, and reflect the ability of approved vasodilator and novel therapeutic interventions to intercept angiogenic remodeling activity in the pulmonary circulation. Validation studies will be performed using living, explanted human lungs affected by PAH using an ex-vivo perfusion approach, to raise confidence in the translatability of these findings. The validation of this approach would constitute a breakthrough in our ability to assess ongoing remodeling in a vascular bed which is ordinarily inaccessible to clinicians, to allow objective stratification of disease severity and rik, tailor pharmacotherapy based on disease activity, and potentially identify therapies acting by entirely novel mechanisms to arrest or reverse disease progression. (End of Abstract)