Novel therapy for Fragile X syndrome

项目概要 脆性 X 综合征 (FXS) 是最常见的遗传性认知障碍形式，也是已知的主要疾病 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制定提高智力的治疗策略 患者的能力。蛋白质合成失调被广泛认为是核心分子异常 与 FXS 相关。由于神经元蛋白质合成对于学习和记忆至关重要，突触的改变 翻译被认为是造成 FXS 智力缺陷的主要原因。目前可用 FXS 的药物干预策略主要治疗行为问题，并且主要集中于 靶向翻译控制的上游以使 FXS 相关表型正常化。我们已经确定了一个具体的 靶点是 mTORC1 和 ERK 信号传导的共同下游效应子，并在 规范翻译。 FXS 动物模型中靶标的基因删除校正了夸大的蛋白质 合成以及与 FXS 相关的其他生化、神经解剖学和行为异常。这些 结果提出了开发 FXS 疾病缓解疗法的策略。通过合理的设计 结合结构蛋白信息和最佳 ADME 特性的方法，我们发现了一种新颖的方法 系列强效抑制剂。 Epigen 针对这一目标开发了特异性的药物样小分子抑制剂， 以先导化合物EPGN1370为例。 STTR 工作第一阶段的主导优化工作 确定 EPGN2036 作为药理学评价的候选药物。该化合物呈剂量依赖性 纠正了口服给药后 FMR1 KO2 小鼠的行为缺陷。此外，EPGN2036 证明 用该化合物治疗的 FMR1 KO 小鼠海马裂解物中的靶标参与。与合作 加州大学圣地亚哥分校的 Alysson Muotri 博士，我们已经开始开发源自 FXS 患者的大脑类器官 在实验室中对疾病进行 3D 建模。大鼠初步安全性研究表明 EPGN2036 具有足够的 安全裕度值得进一步调查。第 2 阶段 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评估 EPGN2036 的功效，评估药物间相互作用的潜力 线索，进行有针对性的备份/后续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 小鼠的脑电图测量结果非常好 与 FXS 患者的脑电图信号一致，并且脑电图可以用作预测早期的生物标志物 疾病调节。因此，我们将评估 EPGN2036 对小鼠 FMR1 KO 小鼠脑电图的影响 和 FXS 脑类器官。在资助期结束时，我们希望能够选择一个开发项目 启动 IND 支持研究并进入人体 1 期临床试验的候选者 评估 EPGN2036 在正常健康志愿者中的安全性和耐受性。

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.