Therapies for Renal Ciliopathies

肾纤毛病的治疗

• 批准号: 10081325
• 金额: $ 3.55万
• 依托单位: CILIOPATHY ALLIANCE
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10081325
• 关键词: Therapies; Renal; Ciliopathies

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 models.

纤毛病是由初级纤毛功能障碍引起的一种罕见而严重的遗传性疾病，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所需的关键信号输出。纤毛功能障碍导致具有高遗传异质性和重叠表型的复杂疾病。尽管临床范围广泛，慢性肾脏疾病（CKD）导致终末期肾脏疾病（ESKD）是整个纤毛病发病率的常见原因。目前，CKD唯一可行的治疗标准是透析和移植。肾纤毛病是儿童期ESKD的主要病因，尽管已经确定了40多种致病基因，但仍然难以预测疾病的严重程度以及外观风险（如果诊断时没有出现）和肾衰竭的进展速度。因此，TheRaCil的目的是：(1)改善高危儿童肾纤毛病患者的诊断和预后；(2)实施针对共同病理通路的治疗方法，通过反义寡核苷酸修饰致病基因或修饰基因的mRNA靶点，并通过重新利用可用分子。这些目标将通过我们独特的欧洲儿童肾纤毛病病例数据库联盟来实现，这将允许更好的患者分层，鉴定修饰基因和疾病进展标记。生物信息学方法将用于整合患者的生物学和遗传数据，以及来自患者样本和临床前模型的多组学和功能分析。这些分析将导致确定共同的可靶向病理途径，以及符合确定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型中进行评估。