Therapies for Renal Ciliopathies

项目概要：纤毛病是由初级纤毛功能障碍引起的一大组罕见和严重的遗传性疾病，初级纤毛是一种基于微管的细胞表面天线，控制发育和组织稳态过程中所需的关键信号输出。纤毛功能障碍导致具有高度遗传异质性和重叠表型的复杂疾病。尽管有广泛的临床谱，但导致终末期肾病（ESKD）的慢性肾病（CKD）是各种纤毛疾病发病的常见原因。目前，CKD唯一可用的护理标准是基于透析和移植。肾纤毛病变是儿童期ESKD的主要原因，尽管已鉴定出40多个致病基因，但仍难以预测疾病的严重程度以及出现风险（如果诊断时不存在）和肾衰竭的进展速度。因此，TheRaCil的目标是：（1）改善处于危险中的小儿肾纤毛病患者的诊断和预后，和（2）实施旨在靶向共有病理途径、通过反义寡核苷酸和通过再利用可用分子来修饰致病或修饰基因的mRNA靶标的治疗方法。这些目标将通过我们在欧洲提供的儿科肾纤毛病变病例的独特数据库的联合来实现，这将允许更好地对患者进行分层，识别修饰基因和疾病进展的标志物。生物信息学方法将用于整合患者的生物和遗传数据以及来自患者样本和临床前模型的多组学和功能分析。这些分析应导致识别共享的靶向病理途径以及符合所识别的新治疗方法的患者，这些新治疗方法将在稳健的临床前模式中进行评价。

Project summary: Project summary Ciliopathies are a large group of rare and severe genetic diseases caused by dysfunction of the primary cilium, a microtubule-based cell surface antenna that controls key signaling output required during development and tissue homeostasis. Cilium dysfunction leads to complex disorders with high genetic heterogeneity and overlapping phenotypes. Despite the broad clinical spectrum, chronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is a common cause of morbidity across ciliopathies. Currently, the only available standard of care for CKD is based on dialysis and transplantation. Renal ciliopathies represent a main cause of ESKD during childhood and despite the identification of more than 40 causative genes, it remains difficult to predict the severity of the disease as well as the risk of appearance (if not present at diagnosis) and the rate of progression of renal failure. TheRaCil therefore aims: (1) to improve diagnosis and prognosis of at risk pediatric renal ciliopathy patients, and (2) to implement therapeutic approaches aimed at targeting shared pathological pathways, at modifying mRNA targets of the causative or modifier genes by antisense oligonucleotides and by the repurposing of available molecules. These goals will be achieved through the federation of our unique databases of pediatric renal ciliopathies cases available across Europe, which will allow a better stratification of patients, the identification of modifier genes and markers of disease progression. Bioinformatics approaches will be used to integrate patients’ biological and genetic data as well as multi-omics and functional analyses from patients samples and preclinical models. These analyses should lead to the identification of shared targetable pathological pathways as well as of patients eligible for the identified new therapeutic approaches which will be evaluated in robust preclinical modes.