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， 靶向翻译控制的上游以使FXS相关表型正常化。我们发现了一种 靶点是mTORC 1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，我们发现了一种新的 一系列有效的抑制剂Epigen已经开发出针对该目标的特异性和药物样小分子抑制剂， 如以先导化合物EPGN 1370为例。在工作的第1阶段STTR部分领导优化工作 将EPGN 2036鉴定为药理学评价的候选物。该化合物呈剂量依赖性 经口给药后纠正FMR 1 KO 2小鼠的行为缺陷。此外，EPGN 2036证明了 在用该化合物处理的FMR 1 KO小鼠的海马裂解物中的靶结合。协同 博士Alysson Muotri在UCSD，我们已经开始开发来自FXS患者的脑类器官， 在实验室里用3D模型模拟疾病。在大鼠中的初步安全性研究表明，EPGN 2036具有足够的 安全边际，以保证进一步调查。该阶段2 SBIR工作的目标是表征临床前 使用药物功效的可翻译生物标志物的EPGN 2036的功效，评估药物-药物相互作用潜力 进行重点备份/随访发现，并评估选定电极导线的安全性，以确定 发展潜力最近的研究表明，FMR 1 KO小鼠的EEG测量结果非常好， 与FXS患者的EEG信号一致，并且EEG可用作预测FXS患者早期的生物标志物。 疾病调节因此，我们将评估EPGN 2036对小鼠FMR 1 KO小鼠EEG和小鼠FMR 2 KO小鼠EEG的影响。 和FXS脑类器官。在补助期结束时，我们希望能够选择一个发展项目， 启动IND使能研究并进展至人类I期临床试验的候选人， 在正常健康志愿者中评估EPGN 2036的安全性和耐受性。

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. Lead optimization efforts in the phase 1 STTR portion of the work identified EPGN2036 as a candidate for pharmacological evaluation. This compound dose-dependently corrected behavioral deficits in FMR1 KO2 mice after oral administration. Moreover, EPGN2036 demonstrated target engagement in hippocampal lysates of FMR1 KO mice treated with the compound. In collaboration with Dr. Alysson Muotri at UCSD, we have started development of brain organoids derived from FXS patients to model the disease in 3D in the laboratory. Preliminary safety studies in rats indicate that EPGN2036 has sufficient safety margin to warrant further investigation. The goal of this phase 2 SBIR work is to characterize the preclinical efficacy of EPGN2036 using a translatable biomarker of drug efficacy, evaluate drug-drug interaction potential of leads, conduct focused back-up / follow-up discovery and assess safety of select leads to determine development potential. Recent work demonstrated that EEG measures in FMR1 KO mice are in excellent agreement with EEG signals of FXS patients and that EEG could be used as a biomarker predictive of early disease modulation. As such, we will evaluate the effect of EPGN2036 on both mouse FMR1 KO mouse EEG and FXS brain organoids. At the end of the grant period, we expect to be in a position to select a development candidate for initiation of IND-enabling studies and progression to phase 1 clinical trials in humans for assessment of safety and tolerability of EPGN2036 in normal healthy volunteers.