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

开发可翻译的神经生理学生物标志物以加速雷特综合征的治疗开发

• 批准号: 10578522
• 负责人: ERIC D MARSH
• 金额: $ 94.17万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578522
• 关键词: 3 year old; Acceleration; Address; Affect; Age; Animal Model; Area; Behavioral; Biological Markers; Clinical; Clinical Trials; Data; Detection; Development; Disease; Disease Progression; Early treatment; Electrodes; Electroencephalography; Evaluation; Evoked Potentials; Genes; Genetic; Goals; Hand; Human; Individual; Life; Link; Measures; Methods; Methyl-CpG-Binding Protein 2; Movement; Mus; Neurodevelopmental Disorder; Neurologic; Persons; Phase; Phenotype; Procedures; Rett Syndrome; Seizures; Severities; Severity of illness; Signal Transduction; Site; Speech; Speed; Symptoms; Technology; Testing; Therapeutic Intervention; Therapeutic Trials; Time; Training; Translations; Walking; Work; biomarker development; candidate identification; clinically relevant; cohort; curative treatments; disease phenotype; genetic testing; human model; improved; insight; loss of function mutation; mouse model; neural circuit; neurophysiology; novel strategies; novel therapeutics; pharmacologic; potential biomarker; pre-clinical; preclinical trial; response biomarker; restoration; skills; therapeutic development; therapy development; tool; treatment response; trial design; visual tracking

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.

RETT综合征（RTT）是由X-的功能突变引起的严重神经发育障碍 连接的基因甲基-CPG结合蛋白2（MECP2），其特征是言语和手工技能的丧失， 走路问题和重复的手动运动。有症状小鼠MECP2的基因恢复可以 反向症状提供希望可以创建疾病改良疗法的希望。阻碍发展 变革性疗法缺乏治疗反应的生物标志物。理想情况下，可以应用生物标志物 在小鼠和人类中，以增强临床前治疗研究的有效翻译并改善人类试验 设计和执行。神经生理评估具有无创的生物标志物的潜力， 测量神经系统变化，并且在人类和动物模型之间可以翻译。 RTT的最新工作， 从我们的小组中发现，受影响人类和小鼠的神经生理学措施的差异 与疾病严重程度相关的模型，但迫切需要识别验证良好且可翻译的模型 RTT中的治疗反应生物标志物。 为了满足这一需求，我们在这里提议开发可以满足特定特定的神经生理生物标志物 主要使用的主要环境（COU），一种早期治疗反应生物标志物，以促进和加快临床前的速度 RTT中新型疗法的临床试验。提案的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生物标志物并建立人类 多站点标准操作程序和规范数据。这些平行项目将是基础 在RTT中确定真正的治疗响应生物标志物。为此，我们将首先确定是否潜在的生物标志物， 定量的脑电图和诱发电位将在RTT的小鼠模型中预测地变化，该模型允许遗传 营救RTT表型。同时，我们将开发并优化标准操作程序 启用候选人神经生理生物标志物的多站点评估。此外，我们将评估 我们正在开发的生物标志物的重测可靠性。最后，我们将确定是否推定 在RTT中，神经生理生物标志物在主动临床变化过程中发生变化。对于R33阶段，我们将 证明我们对候选神经生理生物标志物的人类概念证明在 与RTT的临床试验有关的时间范围，这些生物标志物与RTT临床严重程度相关。 总体而言，该建议利用使用鼠标模型来识别和验证鲁棒的能力 人类神经生理学特征是推定的生物标志物。这些神经生理措施将允许 通过用定量措施替换主观临床发现，加速治疗开发 早期治疗反应。这项工作将共同促进生物标志物开发 介入治疗的发展。