Defining the biologic and physiologic trajectory of presymptomatic through advanced pulmonary fibrosis

项目总结/摘要 肺纤维化（PF）在美国20万人中普遍存在，这一数字正在增加。最 个体表现为进行性呼吸困难和/或咳嗽，并且患有中度晚期疾病， 在诊断时不可逆的纤维化。在早期（临床前）阶段治疗PF将导致 发病率的总体负担有了更大的降低，但对早期自然史的了解有限， 包括生物学和临床进展，仍然是实现这一目标的障碍。提高 了解PF的最早阶段，>450名家族性PF患者的无症状亲属 作为正在进行的 前瞻性队列研究。当定义为异常变化的新发展或进展时， 肺实质（“间质性肺异常”[ILA]），临床前PF大约在 20%的参与者。虽然在首次筛查HRCT上有ILA是疾病进展的主要风险因素，但几乎 一半的临床前PF包括ILA的新发展，强调需要额外的生物标志物， 早期疾病在该队列中，外周血中改变的基因表达先于临床前进展， 并且可能代表有希望的生物标志物。临床上，在那些通过临床前研究进展的参与者中， PF（朝向临床诊断的PF），观察到的进行性生理衰退模式似乎是 疾病阶段特异性和发生的方式，可能会共享与PF个人。重要的是， 用力肺活量（FVC）在临床前PF期间变化很小。FVC用于监测 PF进展，并且是成功的PF疾病改善治疗试验的主要终点。 因此，需要替代终点/结局指标，以研究治疗前的疾病改变。 临床PF。总体假设是PF遵循顺序进展，包括血液生物标志物 （转录组和/或蛋白质）指示早期病理生物学和预测临床前进展，和 关键生理参数的阶段特异性有序衰减。具体目标如下：（1） 定义血液生物标志物特征以预测进行性临床前PF;以及（2）发展疾病 疾病进展模型（DPM）描述PF所有阶段的生理衰减。 已经用于测量疾病改变，使得治疗效果的检测是受试者特异性的， 更强大的替代分析，而不考虑阶段特定的进展预期。工作 将在前瞻性临床前PF队列的持续观察期间检验假设， 完成这些目标是朝着长期目标迈出的重要一步。 （研究者和NHLBI的）计划目标是加速新疾病修饰的开发 治疗PF，特别是那些能够预防或延迟症状发作。

PROJECT SUMMARY/ABSTRACT Pulmonary fibrosis (PF) is prevalent among 200,000 persons in the USA, a figure that is increasing. Most individuals present with progressive dyspnea and/or cough, and have moderately advanced disease with irreversible fibrosis at the time of diagnosis. Treatment of PF at an earlier (pre-clinical) stage would result in a greater reduction in the overall burden of morbidity, but limited understanding of the early natural history, including the biological and clinical progression, remains a barrier to accomplishing this goal. To improve the understanding of the earliest stages of PF, >450 asymptomatic relatives of persons with familial PF have undergone serial screening high resolution CT (HRCT) scans to detect pre-clinical PF, as part of an ongoing prospective cohort study. When defined by the new development or progression of abnormal changes of the pulmonary parenchyma (“interstitial lung abnormalities” [ILA]), pre-clinical PF is observed in approximately 20% of participants. While having ILA on the first screening HRCT is a major risk factor for progression, almost half of pre-clinical PF comprised new development of ILA, underscoring the need for additional biomarkers of early disease. Altered gene expression in the peripheral blood precedes pre-clinical progression in this cohort, and may represent a promising biomarker. Clinically, among those participants progressing through pre-clinical PF (toward clinically-diagnosed PF), the observed pattern of progressive physiologic decay appears to be disease stage-specific and occurs in a manner that may be shared across individuals with PF. Importantly, the forced vital capacity (FVC) undergoes very little change during pre-clinical PF. The FVC is used to monitor for PF progression and has been the primary endpoint in successful trials of disease modifying therapy for PF. Therefore, alternative endpoints/outcome measures are needed in order to study disease modification in pre- clinical PF. The overall hypothesis is that PF follows a sequenced progression, including blood biomarkers (transcriptomic and/or proteins) indicative of early pathobiology and predictive of pre-clinical progression, and a stage-specific, sequenced decay in key physiologic parameters. The following Specific Aims are proposed: (1) Define a blood biomarker signature to predict progressive pre-clinical PF; and (2) Develop a disease progression model (DPM) to describe the physiologic decay across all stages of PF. Disease-specific DPMs have been used to measure disease modification such that detection of a treatment effect is subject-specific, a more powerful alternative to analysis without regard to stage-specific progression expectations. The working hypotheses will be tested during continued observation of the prospective pre-clinical PF cohort and several cohorts of patients with established PF. Completion of these Aims is an important step toward a long-term programmatic goal (of the investigators and the NHLBI) to speed development of new disease modifying therapy for PF, particularly those capable of preventing or delaying symptom onset.