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的最大遗传原因与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。未能治愈与肌萎缩侧索硬化症相关的C9ORF72主要是由于：(I)对神经退行性变的分子发病机制缺乏了解；(Ii)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)由于输送方法低效，包括血脑屏障等因素，阻碍了具有治疗吸引力的分子的输送；(Iv)针对大脑和脊髓病变部位的治疗剂靶向无效。旨在了解肌萎缩侧索硬化症致病基因突变如何导致运动神经元损伤的研究努力，对于开发这些疾病的治疗方法至关重要。与现有C9orf72模型相关的限制可以通过使用特定的患者细胞衍生的名为有机化合物的3D模型来克服。因此，有机化合物作为一种系统，为开发C9ORF72相关神经元损伤的药物或定制基因疗法提供了独特的机会。在这里，我们召集了一个拥有互补专业知识的多学科研究团队，以审查克服其中一些挑战的战略。我们研究计划的总体目标是：(1)从健康人和C9ORF72 ALS/FTD患者的IPSCs中建立3D多细胞有机体模型；(2)利用该联盟已建立的分析方法(如分子标记和电生理学)充分表征新生成的模型；(3)探索ALS中神经元损伤的发生机制；(4)开发C9orf72连锁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..