Hukriede Neil A, Soranno Danielle E, Sander Veronika, Perreau Tayla, Starr Michelle C, Yuen Peter S T, Siskind Leah J, Hutchens Michael P, Davidson Alan J, Burmeister David M, Faubel Sarah, de Caestecker Mark P
Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA.
Department of Paediatrics, University of Colorado, Aurora, USA.
Nat Rev Nephrol. 2022 May;18(5):277-293. doi: 10.1038/s41581-022-00539-2. Epub 2022 Feb 16.
Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI.
人类疾病的临床前模型为治疗方法的发现提供了强大工具，但也存在局限性。这一问题在急性肾损伤（AKI）领域尤为明显，在该领域，临床试验失败被归因于主要在啮齿动物身上进行的不准确建模。诸如肾脏精准医学项目等多学科努力目前已开始识别出人类AKI的分子亚型。此外，在过去十年中，人类多能干细胞衍生的肾脏类器官以及AKI的斑马鱼、啮齿动物和大型动物模型都有了进展。这些类器官和AKI模型正被应用于临床前治疗开发的不同阶段。然而，迄今为止用于评估AKI治疗方法的传统上各自为政、由临床前研究人员主导的方法很少考虑所使用模型系统的局限性，并导致了对不同AKI病理生理学患者临床疗效的错误期望。为解决这一问题，需要开发更灵活、更综合的方法，让具备一系列不同模型系统专业知识的研究人员团队与临床研究人员密切合作，以生成有力的临床前证据，为更有针对性地干预AKI患者提供支持。
