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

项目摘要/摘要 转录因子甲基CpG结合蛋白2(MeCP2)功能缺失突变导致X- 连锁神经发育障碍雷特综合征(RTT)。围绕这个单基因的研究的增长 疾病导致了临床前模型的发展，这些模型概括了诸如刻板印象之类的表型 反复握手、呼吸异常、运动和认知障碍等行为。然而， 仍然缺乏有效的治疗方法。这可以归因于功能的复杂性和多样性 MeCP2的靶标。因此，这项研究建议被制定为探索 治疗发现努力：遗传和药物干预。该提案的设计提供了 申请人有机会接受广泛的神经生理学和神经药理学培训 跨越分子、电生理和行为技术。 近年来，通过基因治疗使MeCP2的表达正常化引起了人们的极大关注 一体式适用于RTT的所有干预措施。然而，不同患者之间MECP2病理突变的差异 引入可能使本已狭窄的治疗指数进一步复杂化的亚群。具体来说，我们 假设具有亚型突变的患者发生不良反应(AEs)的风险更大 模仿一种相关疾病的表型，MECP2重复综合征。行为和电生理 这些可能的MeCP2介导的AEs的呈现被建议通过产生小鼠来评估 既含有特定的亚型突变，又表达野生型MeCP2等位基因。 为了补充遗传方法并绕过这些可能的MeCP2介导的AEs，下游 MeCP2的靶点是代谢性谷氨酸受体3(MGlu3)，它将成为药理学的靶点。MGlu3有 已经被证明在认知中具有功能作用，它的表达一直被证明是 在RTT小鼠模型中降低。我们有初步数据表明mGlu3在 长期突触可塑性；此外，我们产生的数据表明，mGlu3的表达在临床上是 与此相关的是，在患者的脑部尸检样本中，mGlu3mRNA的表达显著降低 临床诊断为RTT。因此，我们假设mGlu3表达减少有助于 RTT的认知表型以及药物增强mGlu3功能将改善这些 RTT模型小鼠的表型。

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.