Stratifying Rett syndrome patient populations to evaluate the efficacy of genetic and pharmacological therapeutic interventions

项目概要/摘要 转录因子甲基CpG结合蛋白2（MeCP 2）的功能缺失突变导致X- 连锁神经发育障碍Rett综合征（RTT）。围绕这种单基因的研究的增长 疾病已经导致临床前模型的发展，该模型概括了表型，如刻板的 重复性绞手行为、呼吸异常以及运动和认知缺陷。然而，在这方面， 仍然缺乏有效的治疗方法。这可以归因于复杂的功能和多样性 MeCP 2的目标。因此，这项研究建议已经开发，以探讨两个武器的 治疗发现努力：遗传和药理干预。该提案的设计提供了 申请人有机会在神经生理学和神经药理学方面进行广泛的培训 跨越分子、电生理和行为技术。 近年来，使用基因治疗使MeCP 2表达正常化作为一种治疗方法已经获得了显著的关注。 适合RTT的所有干预措施。然而，患者之间MECP 2病理突变的差异 引入了可能使已经狭窄的治疗指数进一步复杂化的亚群。我们特别 假设亚型突变患者发生不良反应（AE）的风险更高， 与相关疾病MECP 2复制综合征相似的表型。行为和电生理 这些可能的MeCP 2介导的AE的呈现被提议通过产生小鼠来评估， 携带特异性亚型突变并表达野生型MeCP 2等位基因。 为了补充遗传方法并避免这些可能的MeCP 2介导的AE，下游的 MeCP 2靶向代谢型谷氨酸受体3（mGlu 3）将被靶向。mGlu 3具有 已被证明在认知中具有功能性作用，并且其表达一直被证明是 在小鼠RTT模型中降低。我们有初步的数据表明mGlu 3在 长期突触可塑性;此外，我们已经产生的数据显示，mGlu 3表达在临床上是 相关，因为mGlu 3 mRNA表达在来自患者的脑尸检样品中显著降低 临床诊断为RTT。因此，我们假设mGlu 3表达减少有助于 RTT中的认知表型，并且增强mGlu 3功能的ESTA将改善这些表型， RTT模型小鼠中的表型。

PROJECT SUMMARY/ABSTRACT Loss-of-function mutations in the transcription factor methyl-CpG-binding protein 2 (MeCP2) result in the X- linked neurodevelopmental disorder Rett syndrome (RTT). The growth in research surrounding this monogenic disorder has resulted in development of preclinical models that recapitulate phenotypes such as stereotypic behavior of repetitive hand wringing, breathing abnormalities and deficits in motor and cognition. However, effective therapeutic treatments remain lacking. This can be attributed to the complex functions and diverse targets of MeCP2. Therefore, this research proposal has been developed to explore two arms of the therapeutic discovery efforts: genetic and pharmacological interventions. The design of this proposal provides the opportunity for the applicant to develop a breadth of training in neurophysiology and neuropharmacology spanning molecular, electrophysiological and behavioral techniques. In recent years, normalizing MeCP2 expression using gene therapy has garnered significant attention as a one-size fits all intervention for RTT. However, difference in MECP2 pathological mutations between patients introduces subpopulations that could further complicate an already narrow therapeutic index. Specifically, we hypothesize that patients with hypomorphic mutations could be at a greater risk for adverse effects (AEs) that mimic phenotypes of a related disorder, MECP2 Duplication syndrome. Behavioral and electrophysiological presentations of these possible MeCP2-mediated AEs are proposed to be evaluated by generating mice that harbor both a specific hypomorphic mutation and express a wild-type MeCP2 allele. To complement the genetic approach and circumvent these possible MeCP2-mediated AEs, a downstream target of MeCP2, metabotropic glutamate receptor 3 (mGlu3), will be targeted pharmacologically. mGlu3 has been demonstrated to have a functional role in cognition, and its expression has been consistently shown to be decreased in mouse models of RTT. We have preliminary data that suggests mGlu3 plays a significant role in long-term synaptic plasticity; additionally, we have generated data showing that mGlu3 expression is clinically relevant, as mGlu3 mRNA expression is significantly decreased in brain autopsy samples from patients clinically diagnosed with RTT. Therefore, we hypothesize that decreased mGlu3 expression contributes to cognitive phenotypes in RTT and that pharmacologically potentiating mGlu3 function will improve these phenotypes in RTT model mice.