Drug REpurposing with Artificial intelligence for Muscular disorderS

根据世界卫生组织的数据，到目前为止，只有不到6%的罕见疾病(RDS)拥有批准的治疗方案。根据这一观察，似乎至关重要的是开发能够找到治疗多种RDS的颠覆性方法。为了实现这一目标，梦境将从5种罕见的神经肌肉疾病(NMD)开始，这些疾病具有与自噬功能障碍和结蛋白紊乱相关的共同病理生理学特征。利用来自诱导多能干细胞的骨骼肌细胞(SkMC IPSC)，DREAMS将i)识别5种疾病的共同生物标记物，ii)对所有5种疾病进行高通量药物筛选。通过第一个基于人工智能(AI)的解决方案，药物筛选的输出将用于寻找疾病之间共享的药物靶点。第二个基于人工智能的解决方案将用于为这些共享的药物靶点寻找候选药物(可重复使用的药物和新的分子实体)。第三个基于人工智能的解决方案将用于寻找其他疾病，这些疾病可以通过共享的药物靶点进行治疗，以扩大最有希望的候选药物的适应症。在他们的发现之后，有希望的候选药物将在IPSC和5种NMD以及其他疾病的小鼠模型中进行有效性和安全性测试。同时，DREAMS将设计一项适应性临床试验，为这些具有多个适应症的新药候选药物开发的最后阶段做准备。总而言之，这些技术和概念创新将使DREAMS财团能够：i)开发治疗多种NMD及相关疾病的疗法；ii)创建一种新颖的临床设计，为治疗不同类型RDS患者的药物生成监管途径；iii)加深对RDS共性的科学理解；以及iv)创建可重复使用的药物开发平台，以发现RDS的一般安全有效治疗方法。

According to World Health Organization, to date, fewer than 6% of rare diseases (RDs) have an approved treatment option. In the light of this observation, it appears crucial to develop disruptive approaches that allow to find treatments for multiple RDs. To achieve this goal, DREAMS will start from 5 rare neuromuscular disorders (NMD) that share common pathophysiological characteristics related to dysfunctions of autophagy and desmin disorganization. Using skeletal muscle cells derived from induced pluripotent stem cells (skMC iPSC), DREAMS will i) identify shared biomarkers of the 5 diseases and ii) perform a high throughput drug screen on all 5 diseases. Through a first Artificial Intelligence (AI) based solution, the output of the drug screening will be used to find drug targetsshared between the diseases. A second AI based solution will be used to find drug candidates (repurposable drugs and new molecular entities) for these shared drug targets. A third AI-based solution will be used to find additional diseasesthat could be treated through the shared drug targets, in order to extend the indications for the most promising drug candidates. Following their discoveries, the promising drug candidates will be tested for efficacy and safety in both iPSC and mouse models of the 5 NMDs and additional diseases. In parallel, DREAMS will design an adaptive clinical trial to prepare the final stages of drug development of these novel drug candidates with multiple indications. Together, these technological and conceptual innovations will allow the DREAMS consortium to i) develop therapies to treat multiple NMDs and related diseases, ii) to create a novel clinical design that generates a regulatory pathway for drugs that treat heterogeneous groups of patients suffering from RDs iii) to further the scientific understanding of commonalities in RDs, and iv) to create a reusable drug development platform to discover safe and effective treatments for RDs in general.