Novel therapy for Fragile X syndrome

项目摘要 脆性X综合征（FXS）是认知障碍的最常见的遗传形式，也是已知的最主要的认知障碍。 自闭症的遗传原因FXS是由脆性X智力低下蛋白表达缺失引起的 （FMRP）。FXS研究的一个主要挑战是开发治疗策略， 患者的能力。蛋白质合成失调被广泛认为是一种核心分子异常 与FXS有关。由于神经元蛋白质合成对学习和记忆至关重要， 翻译被认为是导致FXS智力缺陷的主要因素。当前可用 FXS的药物干预策略主要治疗行为问题， 在翻译控制的上游靶点上使FXS相关表型正常化。我们发现了一种 靶点是mTORC1和ERK信号传导的共同下游效应物，并在 规范翻译。FXS校正的夸大蛋白动物模型中靶基因缺失 合成和其他与FXS相关的生化、神经解剖学和行为异常。这些 结果提示了开发FXS的疾病改善治疗剂的策略。通过合理的设计 结合结构蛋白质信息和最佳ADME特性的方法，我们发现了一种 一系列新的强效抑制剂。Epigen为此开发了特异性和药物样小分子抑制剂 靶向，如先导化合物EPGN 1370所例示。我们与Alysson Muotri博士合作， UCSD的实验室提出了一种新的发现范式，用于FXS的有效药物候选化合物 通过使用新开发的大脑类器官或“迷你大脑”在实验室中以3D方式模拟疾病。 第一阶段SBIR工作的目标是对我们新发现的一系列 作为治疗FXS的药剂的新抑制剂。在这项工作中，新的化合物将被确定利用我们的测定 级联组合体外受体药理学、ADME测定和小鼠药代动力学以选择1 - 3 先进的铅分子，将在人类FXS“迷你大脑”中进行评估。最先进的领先 将在FXS的小鼠模型中评估鉴定的生物化学和神经解剖学结果。这 这项工作将为2期详细的体内药理学评估和IND使能研究奠定基础 SBIR。我们的研究将为自闭症谱系障碍的靶向药物开发开辟一条新的途径 例如FXS。

PROJECT SUMMARY Fragile X syndrome (FXS) is the most common inheritable form of cognitive impairment and the leading known genetic cause of autism. FXS is caused by the loss of expression of the fragile X mental retardation protein (FMRP). A major challenge for FXS research is to develop treatment strategies that improve the intellectual capabilities of patients. Dysregulated protein synthesis is widely accepted as a core molecular abnormality associated with FXS. Because neuronal protein synthesis is critical for learning and memory, altered synaptic translation is considered a major contributor to the intellectual deficits seen in FXS. Currently available pharmacological intervention strategies for FXS primarily treat behavioral problems and have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. We have identified a specific target that is a common downstream effector of both mTORC1 and ERK signaling and plays a direct role in regulating translation. Genetic deletion of the target in an animal model of FXS corrected exaggerated protein synthesis and other biochemical, neuroanatomical and behavioral abnormalities associated with FXS. These results suggest a strategy for developing a disease modifying therapeutic for FXS. By using a rational design approach that combines structural protein information and optimal ADME properties, we have discovered a novel series of potent inhibitors. Epigen has developed specific and drug-like small molecule inhibitors to this target, as exemplified by lead compound EPGN1370. We have teamed up with Dr. Alysson Muotri's laboratories at UCSD to propose a novel discovery paradigm for effective drug candidate compounds for FXS by using newly developed cerebral organoids, or “mini-brains” to model the disease in 3D in the laboratory. The goal of this phase 1 SBIR work is to conduct focused lead optimization of our newly discovered series of novel inhibitors as agents to treat FXS. In this work, new compounds will be identified utilizing our assay cascade combining in vitro receptor pharmacology, ADME assays and mouse pharmacokinetics to select 1-3 advanced lead molecules, which will be evaluated in a human FXS “mini-brain”. The best advanced lead identified will be evaluated in a mouse model of FXS for biochemical and neuroanatomical outcomes. This work will set the stage for detailed in vivo pharmacology assessment and IND-enabling studies in the phase 2 SBIR. Our study will open up a new avenue of target-specific drug development for Autism Spectrum Disorders such as FXS.