Development of translatable neurophysiological biomarkers to accelerate therapeutic development in Rett syndrome

Rett综合征(RTT)是一种严重的神经发育障碍，由X-半胱氨酸功能缺失突变引起。 连锁基因甲基CpG结合蛋白2(MECP2)，以言语和手部技能丧失为特征， 行走困难，以及重复的手部动作。MECP2在有症状的小鼠中的遗传恢复可以 逆转症状提供了创造疾病修正疗法的希望。阻碍发展 变革性治疗的关键是缺乏治疗反应的生物标记物。理想情况下，可以应用生物标记物 在小鼠和人类中加强临床前治疗研究的有效转化并改进人体试验 设计和执行。神经生理学评估具有作为生物标志物的潜力，因为它们是非侵入性的， 测量神经变化，并可在人类和动物模型之间转换。在RTT最近的工作， 来自我们小组的研究人员发现，受影响的人类和小鼠的神经生理指标存在差异 与疾病严重程度相关的模型，但迫切需要确定经过充分验证和可翻译的模型 RTT中的治疗反应生物标志物。 为了满足这一需求，我们建议开发神经生理学生物标记物，以满足特定的 初级使用背景(CUU)，一种早期治疗反应生物标记物，促进和加快临床前 以及RTT新疗法的临床试验。建议的R61阶段的主要目标是确定 RTT小鼠模型中疾病改善的候选神经生理学生物标志物和建立人类 多点标准作业程序和规范数据。这些平行项目将是 在RTT中确定一个真正的治疗反应生物标志物。为了做到这一点，我们将首先确定潜在的生物标记物， 定量脑电和诱发电位将在RTT小鼠模型中发生预测性变化，这允许遗传 RTT表型的挽救。同时，我们将制定和优化标准操作程序，以 实现对候选人类神经生理生物标记物的多点评估。此外，我们还将评估 测试-重新测试我们正在开发的生物标志物的可靠性。最后，我们将确定推定的 RTT临床活跃变化过程中神经生理学标志物的变化。对于R33阶段，我们将 证明我们的人类对候选神经生理生物标记物的概念验证在 与RTT临床试验相关的时间框架，以及这些生物标记物与RTT临床严重性相关。 总体而言，该建议利用了使用鼠标模型来识别和验证健壮性的能力 人类神经生理学特征作为推测的生物标志物。这些神经生理学措施将允许 通过用定量措施取代主观临床结果来加速治疗的发展 早期治疗-反应。总之，这项工作将促进生物标记物的开发应用于 介入治疗的发展。

Rett syndrome (RTT), is a severe neurodevelopmental disorder caused by loss-of function mutations in the X- linked gene Methyl-CpG-binding Protein 2 (MECP2) and characterized by loss of speech and hand skills, problems walking, and repetitive hand movements. Genetic restoration of MECP2 in symptomatic mice can reverse symptoms providing hope that disease-modifying therapies can be created. Impeding the development of transformative therapies are a lack of biomarkers of treatment-response. Ideally, a biomarker can be applied in mice and humans to enhance effective translation of preclinical treatment studies and improve human trial design and execution. Neurophysiological assessments have potential as biomarkers as they are non-invasive, measure neurological changes, and are translatable between humans and animal models. Recent work in RTT, from our group, has found differences in neurophysiological measures in both affected humans and mouse models that correlate with disease severity, but an urgent need exists to identify well-validated and translatable treatment-response biomarkers in RTT. To address this need, we propose here to develop neurophysiological biomarkers that can fulfil a specific primary Context of Use (COU), an early treatment response biomarker, to facilitate and speed both preclinical and clinical trials of novel therapies in RTT. The primary goal of the R61 phase of the proposal is to identify candidate neurophysiological biomarkers of disease improvement in a mouse model of RTT and establish human multi-site standard operating procedures and normative data. These parallel projects will be foundational to identify a true treatment responsive biomarker in RTT. To do this we will first determine if potential biomarkers, quantitative EEG and evoked potentials will change predictively in a mouse model of RTT that allows for genetic rescue of the RTT phenotype. Simultaneously, we will develop and optimize standard operating procedures to enable multi-site evaluation of candidate human neurophysiological biomarkers. Additionally, we will evaluate test-retest reliability of the biomarkers we are developing. Finally, we will determine if the putative neurophysiological biomarkers change during active clinical change in RTT. For the R33 phase, we will demonstrate that our human proof-of-concept of candidate neurophysiological biomarkers are stable over the time frame relevant to clinical trials in RTT and that these biomarkers correlate with RTT clinical severity. Overall, this proposal takes advantage of the ability to use mouse models to identify and validate robust human neurophysiological features as putative biomarkers. These neurophysiological measures will allow for accelerated therapy development via the replacement of subjective clinical findings with quantitative measures of early treatment-response. Together, this work will facilitate biomarker development to be employed in interventional therapy development.