Mitochondrial and metabolic dysfunctions in the progeroid Cockayne syndromeand therapeutic perspectives

柯凯因综合征（CS）是一种罕见的遗传性疾病，表现为显著的早衰，严重的神经缺陷，紫外线过敏，预期寿命短，迄今尚无治疗方法。该项目基于最近对CS患者细胞中缺陷通路的鉴定和验证，该通路与文献记载的DNA修复缺陷解耦，而涉及线粒体和代谢损伤。在分子和细胞水平上，这种代谢损伤的程度和后果仍有待阐明，这是本提案的主要主题。重要的是，CS表现出广泛的严重程度，构成临床连续体，其原因尚不清楚。我们的工作假设是代谢改变在很大程度上导致了CS的不同临床结果。除了不平衡的能量学，代谢变化影响调控途径，对活性氧的保护和表观遗传景观。我们的目标是剖析CS的代谢损伤及其对细胞功能的影响，并为包括代谢对衰老过程的保护作用在内的治疗干预铺平道路。事实上，我们之前已经证明的卟啉衍生物mntpap可以完全挽救CS细胞的改变，这是一种新疗法的关键因素。MnTBAP获得了CS的孤儿药指定，并且在体内具有良好的耐受性。本应用程序有三个主要目的。目的1：将CS临床症状的严重程度与线粒体参数的改变联系起来，从而对mntpap治疗产生反应的易感性。为此，我们将评估线粒体损伤及其通过治疗的挽救。目标2。利用主要代谢途径及其对ROS的保护作用的系统方法，将CS缺陷与患者细胞的代谢变化联系起来。患者细胞的结果将与联盟成员开发的疾病特异性评分系统相结合。目标3。评估CS-iPS细胞、神经外胚层类器官（只有我们的研究团队从CS-iPS细胞中产生）线粒体和代谢改变的程度。我们将在这些细胞/结构上应用上述方法，并将整合mntpap效果的临床前数据。该项目依赖于新概念的结合，患者来源的生物材料的独特收集，以及研究科学家和临床医生之间的直接联系，以剖析潜在的原因，并为CS的治疗干预打开道路。

Cockayne syndrome (CS) is a rare genetic disease displaying dramatically precocious ageing, severe neurological defects, UV-hypersensitivity, and a short life expectancy with no treatment to date. This project is based on the recent identification and validation of a defective pathway in cells of CS patients that is uncoupled from the well-documented DNA repair defect, and rather involves mitochondrial and metabolic impairment. The extent and the consequences of this metabolic impairment at the molecular and cellular level remain to be elucidated and are the main subject of the present proposal. Importantly, CS displays a wide spectrum of severity that constitutes a clinical continuum the reasons of which are not understood. Our working hypothesis is that metabolic alterations are largely responsible for the different clinical outcomes in CS. Beyond unbalanced energetics, metabolic changes affect regulatory pathways, protection from ROS, and the epigenetic landscape.Our objective is to dissect the metabolic impairment in CS and its consequences on cellfunction, and pave the way to a therapeutic intervention that includes protective effects of metabolism against the aging process. Indeed, the full rescue of CS cellular alterations by a porphyrin derivative acting on oxidative and nitrosative stress, MnTBAP, that we previously demonstrated, is the key element for a novel therapy. MnTBAP obtained an Orphan Drug Designation for CS and is well tolerated in vivo. The present application has three primary aims. Aim1: Link the severity of CS clinical symptoms, and thereby the susceptibility to respond to MnTBAP treatment, to altered mitochondrial parameters. For this, we will assess mitochondrial impairment and its rescue by treatment. Aim 2. Link CS defects with metabolic changes in patient cells using a systematic approach to major metabolic pathways and their protective effect against ROS. Results in patient cells will be integrated with the disease specific scoring system developed by consortium members. Aim 3. Assess the extent of mitochondrial and metabolic alterations on CS-derived iPS cells, neuroectodermal organoids (that only our consortium has produced from CS-iPS cells). On these cells/structures will be applied the abovementioned approaches, and we will consolidate preclinical data on the effect MnTBAP. This project relies on a combination of novel concepts, a unique collection of patient-derived biomaterial, and direct link between research scientists and clinicians to dissect the underlying causes and open to a therapeutic intervention for CS.