The Idealised Lung Clearance Index: tuning in to the silent years of cystic fibrosis

理想的肺清除指数：适应囊性纤维化的沉默岁月

基本信息

批准号：
EP/T001186/1
负责人：
Grant Ritchie
金额：
$ 58.78万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FT001186%2F1
关键词：
Idealised Lung Clearance Index tuning

项目摘要

This proposal deals with an emerging and disruptive technology known as molecular flow sensing (MFS) of human breath. MFS allows highly precise and accurate measures of gas flows and concentrations such that a simple non-invasive breath test can be used to detect the onset of early stage airways disease, potentially of great strategic significance as the societal and financial costs of chronic airways disease are huge. The difficulty in identifying the presence of early airways disease and tracking change in disease state (progression or regression) with precision remains a serious problem for both medicine and industry. The standard approach of spirometry (for example, measuring how much air you can breathe out in a given time) does not identify the presence of disease in the lung until the pathology is well established, and this limits the opportunity for early intervention before there is significant irreversible structural damage within the lung. However, it is very difficult to justify starting expensive therapies without clear evidence from a marker showing the early presence of disease. In industry, an ability to track changes in lung function with precision would reduce greatly the number of patients that need to be recruited for a clinical trial. In turn, this would significantly reduce costs and addresses a major bottleneck in the whole drug development pipeline. Finally, the cost of new drugs is such that it will be impossible to use them without first determining which patients will benefit most. The unprecedented precision and accuracy of MFS technology has the potential to provide an early marker of pathology through the measurement of the inhomogeneity of the lung and thereby address many of the issues highlighted above. This proposal specifically relates to the development of MFS technology for use with pre-school children with cystic fibrosis where a "window of opportunity" exists for early diagnosis of lung disease and intervention. Here, there are two technical requirements: (i) to reduce the timescale for the breath test, and (ii) to reduce the size of the instrument. Requirement (i) will be addressed by incorporating trace amounts of an inert gas into the inspired air to allow the time taken for it to sample the lungs to be obtained contemporaneously with "air" breathing data. Requirement (ii) will be achieved by miniaturizing the MFS device while retaining sufficiently high enough precision and accuracy to realise measures of lung inhomogeneity. The MFS method is the first that seeks to separate inhomogeneity in alveolar ventilation into a component that arises because of inhomogeneity in the way the lung inflates and another that represents the inhomogeneity in the amount of deadspace; as such, it has the potential to separate reversible from irreversible abnormalities in CF lung disease. The normally used Lung Clearance Index (LCI) cannot differentiate between irreversible structural damage and airway narrowing due to mucus secretion. This fact further highlights the disruptive nature of MFS technology.MFS technology directly addresses the core need for better ways of measuring lung disease, both for the development of novel therapeutics and for better management of patients with existing therapeutic options. As more novel therapeutic interventions become available that directly target the dysfunctional CF transmembrane conductance regulator, the quantitative data using the MFS may prove suitable to establish whether novel CF drug treatments will impact lung function measurements over time in young children where early intervention with effective treatments could have the most pronounced long-term effect.

该建议涉及一种被称为人类呼吸的分子流动感（MF）的新兴和破坏性技术。 MFS可以高度精确，准确地测量气体流量和浓度，从而可以使用简单的非侵入性呼气测试来检测早期航空疾病的发作，这可能具有巨大的战略意义，因为慢性气道疾病的社会和财务成本很大。难以确定早期气道疾病的存在并以精度跟踪疾病状态（进展或回归）的变化仍然是医学和工业的严重问题。肺活量测定法的标准方法（例如，测量在给定时间内可以呼吸多少空气）直到病理良好直到肺部的存在，这限制了早期干预的机会，然后肺部内有明显的不可逆结构损害。但是，如果没有明确的疾病出现的标志物，就很难证明开始昂贵的疗法是合理的。在行业中，以精度跟踪肺功能变化的能力将大大减少需要招募进行临床试验的患者数量。反过来，这将大大降低成本，并解决整个药物开发管道中的主要瓶颈。最后，新药的成本使得不首先确定哪些患者将受益最大，就无法使用它们。 MFS技术的前所未有的精度和准确性有可能通过测量肺的不均匀性来提供早期的病理标志，从而解决了上面突出的许多问题。该建议特别涉及MFS技术的开发，用于与患有囊性纤维化的学龄前儿童一起使用，其中存在“机会之窗”，用于早期诊断出肺部疾病和干预措施。在这里，有两个技术要求：（i）减少呼气测试的时间尺度，以及（ii）减少仪器的大小。要求（i）通过将痕量的惰性气体纳入受启发的空气中，以使其花费的时间与“空气”呼吸数据同时获得肺部采样。要求（II）通过小型化MFS设备来实现（II），同时保持足够高的精度和准确性，以实现肺部不均匀性的措施。 MFS方法是第一个试图将肺泡通气中的不均匀性分离为由于肺膨胀的方式不均匀而产生的成分，而另一种代表死空区数量不均匀的成分；因此，它有可能将可逆的可逆性与CF肺部疾病中不可逆的异常分开。通常使用的肺部清除指数（LCI）无法区分不可逆的结构损伤和由于粘液分泌而导致的气道变窄。这一事实进一步凸显了MFS技术的破坏性。MFS技术直接解决了更好地测量肺部疾病的核心需求，包括开发新型治疗剂，以及更好地管理具有现有治疗选择的患者。随着更新颖的治疗干预措施成为可直接针对功能障碍的CF跨膜电导调节剂，使用MFS的定量数据可能证明是可以证明，可以确定新型CF药物治疗是否会影响幼儿的肺功能测量是否会在早期干预中使用有效治疗的早期干预可能具有最明显的长期长期效应。