EURAS: EUropean network for neurodevelopmental RASopathies

颜面皮肤综合征、Costello综合征和SYNGAP 1相关脑病是罕见的神经发育性RASopathies，表现为严重的智力残疾、癫痫发作和自闭症谱系障碍。这些症状诊断不足，缺乏批准的治疗方案。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研究，用于患者队列分层和治疗评价。为了阐明RASopathies的病理生理学，并确定细胞/分子“疾病特征”作为药物筛选和治疗验证的生物标志物，EURAS将生成新的并使用现有的疾病模型。将在分化的、电活性的患者iPSC衍生的神经元上进行由自动化高分辨率、高内容管道辅助的药物库的表型筛选。将进行临床前概念验证试验，使用重新设计的药物，反义寡核苷酸和运动认知训练，以实现动物模型中癫痫发作和自闭症行为特征的逆转。为了向患者提供侵入性较小的治疗，将开发和验证用于向大脑有效递送药物治疗的新技术。最后，EURAS建立了全欧洲患者协会，以提高受影响家庭的认识和交流，并促进他们获得知识和治疗。通过所有这些措施，EURAS提供了新的有效疗法，并为RASopathies的神经系统症状的早期和准确诊断建立了框架，目前还没有。此外，EURAS的一些结果将是广泛可转移的，甚至促进不相关疾病的治疗方法的发展。因此，EURAS将可持续地改善受影响人民的生活，并加强欧洲和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.