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

基本信息

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
项目类别：
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

项目摘要

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) 是一种严重的神经发育障碍，由 X 染色体功能丧失突变引起连锁基因甲基 CpG 结合蛋白 2 (MECP2)，其特征是言语和手部技能丧失，行走问题和重复的手部动作。有症状的小鼠中 MECP2 的基因恢复可以逆转症状为创造疾病缓解疗法带来了希望。阻碍发展变革性疗法的主要缺点是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，测量神经系统变化，并且可以在人类和动物模型之间进行转换。最近在 RTT 方面的工作，我们小组发现受影响的人类和小鼠的神经生理学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转化的模型 RTT 中的治疗反应生物标志物。为了满足这一需求，我们在此建议开发能够满足特定需求的神经生理学生物标志物主要使用背景 (COU)，一种早期治疗反应生物标志物，可促进和加速临床前研究 RTT 中新疗法的临床试验。该提案 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并建立人类多站点标准操作流程和规范数据。这些并行项目将成为基础确定 RTT 中真正的治疗反应性生物标志物。为此，我们将首先确定潜在的生物标志物，定量脑电图和诱发电位将在 RTT 小鼠模型中发生预测性变化，该模型允许遗传 RTT表型的拯救。同时，我们将制定和优化标准操作流程，以能够对候选人类神经生理学生物标志物进行多位点评估。此外，我们将评估我们正在开发的生物标志物的反复测试可靠性。最后，我们将确定假设的神经生理学生物标志物在 RTT 的活跃临床变化期间发生变化。对于 R33 阶段，我们将证明我们对候选神经生理学生物标志物的人类概念验证在与 RTT 临床试验相关的时间框架以及这些生物标志物与 RTT 临床严重程度相关。总体而言，该提案利用了使用小鼠模型来识别和验证稳健性的能力人类神经生理学特征作为假定的生物标志物。这些神经生理学措施将允许通过用定量测量代替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开发，用于介入治疗的发展。