EURAS: EUropean network for neurodevelopmental RASopathies

心-面-皮综合征、Costello综合征和syngap1相关脑病是罕见的神经发育性rasopathy，表现为严重的智力障碍、癫痫发作和自闭症谱系障碍。这些症状未得到充分诊断，也缺乏经批准的治疗方案。EURAS旨在为RASopathies开发新的有效疗法和手术疾病管理。在来自13个国家的患者组织的大力支持下，将实施一项新的基于患者报告的登记，用于患者队列分层和治疗评估。为了阐明ras病变的病理生理学，并识别细胞/分子“疾病特征”作为药物筛选和治疗验证的生物标志物，EURAS将生成新的和采用现有的疾病模型。在自动化高分辨率、高含量管道的协助下，药物文库的表型筛选将在分化的、电活性的患者ipsc来源的神经元上进行。临床前概念验证试验将使用改进型药物、反义寡核苷酸和运动认知训练，以在动物模型中实现癫痫发作和自闭症行为特征的逆转。为了给患者提供更少的侵入性治疗，将开发和验证有效的药物输送到大脑的新技术。最后，EURAS建立了全欧洲范围的患者协会，以提高受影响家庭之间的认识和交流，并促进他们获得知识和治疗。通过所有这些措施，EURAS提供了新的有效治疗方法，并为RASopathies的早期和准确诊断神经症状奠定了框架，这是目前无法实现的。此外，EURAS的一些结果将被广泛转移，甚至促进对不相关疾病的治疗的发展。因此，EURAS将持续改善受影响人群的生活，并加强欧洲和全世界卫生系统的专业知识。

Cardio-facio-cutaneous syndrome, Costello syndrome and SYNGAP1-related encephalopathy are rare neurodevelopmental RASopathies manifesting with severe intellectual disability, seizures and autism spectrum disorder. These symptoms are underdiagnosed and lack approved therapeutic options. EURAS aims to develop new effective therapies and operative disease management for RASopathies. With strong support of patient organizations from 13 countries, a new patient report-based registry for stratification of patient cohorts and evaluation of treatments will be implemented. To clarify the pathophysiology of RASopathies and to identify cellular/molecular “disease signatures” as biomarkers for drug screening and for therapy validation, EURAS will generate new and employ existing disease models. Phenotypical screenings of drug libraries assisted by automated high-resolution, high-content pipelines will be conducted on differentiated, electrically active patient iPSC-derived neurons. Preclinical proof-of-concept trials with repurposed drugs, antisense oligonucleotides and motor-cognitive training will be performed to achieve reversal of seizures and autistic behavioural traits in animal models. To provide patients with less invasive treatments, new technologies for efficient drug delivery of treatments to the brain will be developed and validated. Finally, EURAS establishes Europe-wide patient association to improve awareness and exchange between affected families and to foster their access to knowledge and therapies. With all these measures, EURAS delivers new effective therapies and set the frame for early and accurate diagnosis of neurological symptoms in RASopathies, which are not available at present. Moreover, some results of EURAS will be widely transferable, fostering development of therapies even for unrelated diseases. Thus, EURAS will sustainably improve the lives of affected people and strengthen expertise of health systems in Europe and worldwide.