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

肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）是毁灭性的疾病。ALS和FTD的大多数遗传原因与C9 ORF 72基因突变有关。虽然最近在ALS/FTD的遗传学方面有了重大发现，但患者仍然没有真实的治疗方法。ALS连锁的C9 ORF 72的任何治愈的缺乏主要归因于：（i）对神经变性的分子发病机理的理解不足;（ii）缺乏模拟人类疾病的多细胞和多机制复杂性的可靠动物模型;（iii）治疗上有吸引力的分子的递送受到低效递送方法的阻碍，所述递送方法包括如血脑屏障的因素;（iv）将治疗剂特异性靶向脑和脊髓的患病部位无效。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这些疾病的治疗开发至关重要。与现有C9 orf 72模型相关的限制可以通过使用特定的患者细胞衍生的3D模型来克服，称为类器官。因此，类器官提供了独特的机会，作为开发用于C9 ORF 72相关神经元损伤的药理学或定制基因疗法的系统。在这里，我们组建了一个多学科的研究团队，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C9 ORF 72 ALS/FTD患者的iPSC中生成3D体外多细胞类器官模型;（2）使用联盟中已建立的测定方法完全验证新生成的模型。（例如分子标记和电生理学）;（3）探索ALS中神经元损伤如何发生;（4）开发C9 orf 72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..