JPND - Multicellular organoids: modeling, mechanisms and therapy development for C9ORF72-associated neurodegeneration.

肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是毁灭性的疾病。ALS和FTD的最主要遗传原因与C9ORF72基因突变有关。虽然最近在ALS/FTD的遗传学方面取得了重大发现，但患者仍然没有真正的治疗方法。als相关C9ORF72缺乏任何治愈方法主要归因于：(i)对神经变性的分子发病机制了解不足；（二）缺乏模拟人类疾病多细胞和多机制复杂性的可靠动物模型；（iii）具有治疗吸引力的分子的输送受到低效率的输送方法的阻碍，包括血脑屏障等因素；（iv）治疗药物特异性靶向脑和脊髓病变部位无效。旨在了解ALS致病基因突变如何导致运动神经元损伤的研究工作对于促进这些疾病的治疗发展至关重要。现有C9orf72模型的局限性可以通过使用特定的患者细胞衍生的3D模型来克服，这些模型被称为类器官。因此，类器官为开发针对c9orf72相关神经元损伤的药理学或定制基因疗法提供了独特的机会。在这里，我们组建了一个多学科研究团队，他们拥有互补的专业知识，以研究克服这些挑战的策略。我们的研究计划的总体目标是：(1)从健康和C9ORF72 ALS/FTD患者的iPSCs中生成3D体外多细胞类器官模型；(2)使用联盟中建立的分析（例如分子标记和电生理学）充分表征新生成的模型；(3)探讨ALS患者神经元损伤的发生机制；(4)开发C9orf72相关ALS的治疗方法。

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating disorders. The most genetic cause of ALS and FTD is linked to mutations in C9ORF72 gene. While significant discoveries have recently been made in the genetics of ALS/FTD, patients still have no real therapeutic treatments. The lack of any cure for ALS-linked C9ORF72 is attributable primarily to: (i) Poor understanding of the molecular pathogenesis of neurodegeneration; (ii) Lack of reliable animal models mimicking the multicellular and multi-mechanism complexity of the human disease; (iii) Delivery of therapeutically attractive molecules has been hampered by inefficient delivery methods including factors like the blood-brain barrier; (iv) Ineffective targeting of therapeutic agents specifically to the diseased sites of the brain and spinal cord. Research efforts aimed at understanding how mutations in ALS causative genes leads to motor neuron injury are of the utmost importance to enable therapeutic development for these disorders. The limitations associated with existing C9orf72 models can be overcome by using specific patient cells - derived 3D models named organoids. Thus, organoids provide unique opportunities as a system for the development of pharmacological or tailored gene therapies for C9ORF72-linked neuronal injury. Here, we assembled a multidisciplinary research team with complimentary expertise to examine strategies to overcome some of these challenges. The overall aims of our research programme are: (1) Generate 3D in vitro multicellular organoids models from iPSCs derived from healthy and patients with C9ORF72 ALS/FTD; (2) Fully characterise the newly generated models using established assays in the consortium (e.g. molecular markers and electrophysiology); (3) Explore how neuronal injury happen in ALS; (4) develop treatment for C9orf72 linked ALS..