An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis
An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2017-0096st
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发表时间：
2017-05-01
影响因子：
6.4
通讯作者：
White, Eric S.
中科院分区：
文献类型：
--
作者：
Jenkins, R. Gisli;Moore, Bethany B.;White, Eric S.
许多化合物已经在动物模型上显示出限制肺纤维化发展的有效性，但这些化合物中很少有化合物在临床试验中复制这些有益的效果。鉴于在特发性肺纤维化(IPF)患者中进行临床试验所面临的挑战，临床前数据包在分析和解释方面必须具有健壮性，以便有最好的机会选择有前途的候选药物进行临床试验。美国胸科学会召集了一个肺纤维化专家小组，讨论并正式提出抗纤维化化合物的临床前评估建议。专家小组考虑了三个主要主题(动物的选择，纤维化模型的实际考虑，以及评估的纤维化终点)。认识到需要实际考虑，我们采取了务实的做法。普遍的观点是，在不同性别的动物身上使用小鼠气管内博莱霉素模型，使用羟脯氨酸测量胶原积累并进行组织学评估，是可用于临床前测试的最具特征性的动物模型。建议在急性炎症期消退后(通常在第7天之后)进行该模型中抗纤维化化合物的测试。稳健的分析还可能包括对人类IPF样本的验证性研究，以及使用体内或体外方法在第二个系统中验证结果。该小组还强烈鼓励公布阴性结果，以告知肺纤维化界。这些建议仅用于临床前治疗评估，并不是为了阻止新兴技术的发展，以更好地了解IPF的发病机制。
Numerous compounds have shown efficacy in limiting development of pulmonary fibrosis using animal models, yet few of these compounds have replicated these beneficial effects in clinical trials. Given the challenges associated with performing clinical trials in patients with idiopathic pulmonary fibrosis (IPF), it is imperative that preclinical data packages be robust in their analyses and interpretations to have the best chance of selecting promising drug candidates to advance to clinical trials. The American Thoracic Society has convened a group of experts in lung fibrosis to discuss and formalize recommendations for preclinical assessment of antifibrotic compounds. The panel considered three major themes (choice of animal, practical considerations of fibrosis modeling, and fibrotic endpoints for evaluation). Recognizing the need for practical considerations, we have taken a pragmatic approach. The consensus view is that use of the murine intratracheal bleomycin model in animals of both genders, using hydroxyproline measurements for collagen accumulation along with histologic assessments, is the best-characterized animal model available for preclinical testing. Testing of antifibrotic compounds in this model is recommended to occur after the acute inflammatory phase has subsided (generally after Day 7). Robust analyses may also include confirmatory studies in human IPF specimens and validation of results in a second system using in vivo or in vitro approaches. The panel also strongly encourages the publication of negative results to inform the lung fibrosis community. These recommendations are for preclinical therapeutic evaluation only and are not intended to dissuade development of emerging technologies to better understand IPF pathogenesis.