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- 连锁基因甲基-CpG-结合蛋白2（MECP 2）并以丧失语言和手部技能为特征， 行走困难和重复的手部动作。在有症状的小鼠中MECP 2的遗传恢复可以 逆转症状，为创造改善疾病的疗法提供了希望。阻碍发展 缺乏治疗反应的生物标志物。理想情况下，生物标志物可以应用于 在小鼠和人类中，以增强临床前治疗研究的有效转化并改善人体试验 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， 测量神经系统的变化，并且可以在人类和动物模型之间转换。最近在RTT的工作， 在受影响的人类和小鼠中发现了神经生理学测量的差异 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 RTT中的治疗反应生物标志物。 为了解决这一需求，我们在这里提出开发神经生理学生物标志物，可以实现特定的 主要使用背景（COU），一种早期治疗反应生物标志物，以促进和加速临床前 以及RTT新疗法的临床试验。建议书R61阶段的主要目标是确定 在RTT小鼠模型中的疾病改善的候选神经生理学生物标志物，并建立人 多站点标准操作程序和规范数据。这些并行项目将是基础， 在RTT中鉴定真正治疗响应性生物标志物。为此，我们将首先确定潜在的生物标志物， 定量EEG和诱发电位将在RTT小鼠模型中预测性地改变， 拯救RTT表型。同时，我们将制定和优化标准操作程序， 能够对候选人神经生理学生物标志物进行多位点评价。此外，我们将评估 我们正在开发的生物标志物的重测信度。最后，我们将确定假定的 在RTT的活跃临床变化期间，神经生理学生物标志物发生变化。对于R33阶段，我们将 这表明我们的候选神经生理学生物标志物的人类概念验证在整个过程中是稳定的。 这些生物标志物与RTT临床试验相关，并且这些生物标志物与RTT临床严重程度相关。 总的来说，该提案利用了使用小鼠模型来识别和验证鲁棒性的能力。 人类神经生理学特征作为推定的生物标志物。这些神经生理学措施将允许 通过用定量测量替代主观临床结果加速治疗开发 早期治疗反应。总之，这项工作将促进生物标志物的发展，以用于 介入治疗发展。

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.