Novel therapy for Fragile X syndrome

项目总结 脆性X综合征(FXS)是认知损害最常见的遗传性形式，也是已知最主要的 自闭症的遗传原因。FXS是由脆性X智力低下蛋白的表达缺失引起的 (FMRP)。FXS研究的一个主要挑战是开发治疗策略，以提高智力 病人的能力。蛋白质合成失调被广泛认为是一种核心分子异常。 与FXS关联。由于神经元蛋白质合成对学习和记忆至关重要，因此改变突触 翻译被认为是FXS中智力缺陷的主要原因。目前可用 FXS的药物干预策略主要用于治疗行为问题，并主要集中在 翻译控制上游的目标，以使FXS相关表型正常化。我们已经确定了一种特定的 靶点是mTORC1和ERK信号的共同下游效应者，并在 规范翻译。FXS校正的夸大蛋白动物模型中靶基因的缺失 与FXS相关的合成和其他生化、神经解剖学和行为异常。这些 结果提示了一种开发FXS疾病修正疗法的策略。通过使用合理的设计 结合结构蛋白质信息和最佳ADME性质的方法，我们发现了一种新的 一系列有效的抑制剂。EpiGen已经开发出针对这一靶点的特定和类似药物的小分子抑制剂， 如先导化合物EPGN1370所示。领导工作的第一阶段STTR部分的优化工作 将EPGN2036确定为进行药理评价的候选药物。该化合物呈剂量依赖性 纠正FMR1KO2小鼠灌胃给药后的行为缺陷。此外，EPGN2036还展示了 用该化合物处理的FMR1 KO小鼠海马区裂解产物中的靶参与。与 加州大学圣迭戈分校的Alysson Muotri博士说，我们已经开始开发从FXS患者中提取的脑器官类化合物 在实验室里用3D模型制作疾病模型。对大鼠的初步安全性研究表明，EPGN2036有足够的 安全边际，以保证进一步调查。这项第二阶段SBIR工作的目标是描述临床前 EPGN2036使用可翻译的药效生物标志物评价药物相互作用潜力 对线索进行有重点的后备/跟踪发现，并评估选定线索的安全性以确定 发展潜力。最近的工作表明，FMR1 KO小鼠的脑电测量结果非常好 与FXS患者的脑电信号一致，EEG可作为预测早期FXS的生物标志物 疾病调节。因此，我们将评估EPGN2036对小鼠FMR1 KO小鼠脑电的影响 和FXS脑有机化合物。在授权期结束时，我们希望能够选择一个开发项目 启动IND使能研究并进展到人类临床试验第一阶段的候选对象 EPGN2036在正常健康志愿者中的安全性和耐受性评价

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.