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:
- 金额:$ 94.17万
- 依托单位:
- 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:
- 关键词:3 year oldAccelerationAddressAffectAgeAnimal ModelAreaBehavioralBiological MarkersClinicalClinical TrialsDataDetectionDevelopmentDiseaseDisease ProgressionEarly treatmentElectrodesElectroencephalographyEvaluationEvoked PotentialsGenesGeneticGoalsHandHumanIndividualLifeLinkMeasuresMethodsMethyl-CpG-Binding Protein 2MovementMusNeurodevelopmental DisorderNeurologicPersonsPhasePhenotypeProceduresRett SyndromeSeizuresSeveritiesSeverity of illnessSignal TransductionSiteSpeechSpeedSymptomsTechnologyTestingTherapeutic InterventionTherapeutic TrialsTimeTrainingTranslationsWalkingWorkbiomarker developmentcandidate identificationclinically relevantcohortcurative treatmentsdisease phenotypegenetic testinghuman modelimprovedinsightloss of function mutationmouse modelneural circuitneurophysiologynovel strategiesnovel therapeuticspharmacologicpotential biomarkerpre-clinicalpreclinical trialresponse biomarkerrestorationskillstherapeutic developmenttherapy developmenttooltreatment responsetrial designvisual 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-染色体功能缺失突变引起
项目成果
期刊论文数量(0)
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{{ truncateString('ERIC D MARSH', 18)}}的其他基金
The Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/Penn
CHOP/宾夕法尼亚大学智力与发育障碍研究中心 (IDDRC)
- 批准号:
10678888 - 财政年份:2021
- 资助金额:
$ 94.17万 - 项目类别:
The Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/Penn
CHOP/宾夕法尼亚大学智力与发育障碍研究中心 (IDDRC)
- 批准号:
10450692 - 财政年份:2021
- 资助金额:
$ 94.17万 - 项目类别:
Seizure generation and network excitability in Arx related Infantile Spasms
Arx 相关婴儿痉挛症中的癫痫发作和网络兴奋性
- 批准号:
8728339 - 财政年份:2013
- 资助金额:
$ 94.17万 - 项目类别:
Seizure generation and network excitability in Arx related Infantile Spasms
Arx 相关婴儿痉挛症中的癫痫发作和网络兴奋性
- 批准号:
8631719 - 财政年份:2013
- 资助金额:
$ 94.17万 - 项目类别:
Seizure generation and network excitability in Arx related Infantile Spasms
Arx 相关婴儿痉挛症中的癫痫发作和网络兴奋性
- 批准号:
8840331 - 财政年份:2013
- 资助金额:
$ 94.17万 - 项目类别:
ARX related Interneuron dysfunction and intractable pediatric epilepsy
ARX相关的中间神经元功能障碍和顽固性小儿癫痫
- 批准号:
8695497 - 财政年份:2010
- 资助金额:
$ 94.17万 - 项目类别:
ARX related Interneuron dysfunction and intractable pediatric epilepsy
ARX相关的中间神经元功能障碍和顽固性小儿癫痫
- 批准号:
8270485 - 财政年份:2010
- 资助金额:
$ 94.17万 - 项目类别:
ARX related Interneuron dysfunction and intractable pediatric epilepsy
ARX相关的中间神经元功能障碍和顽固性小儿癫痫
- 批准号:
8049636 - 财政年份:2010
- 资助金额:
$ 94.17万 - 项目类别:
ARX related Interneuron dysfunction and intractable pediatric epilepsy
ARX相关的中间神经元功能障碍和顽固性小儿癫痫
- 批准号:
7894214 - 财政年份:2010
- 资助金额:
$ 94.17万 - 项目类别:
ARX related Interneuron dysfunction and intractable pediatric epilepsy
ARX相关的中间神经元功能障碍和顽固性小儿癫痫
- 批准号:
8471211 - 财政年份:2010
- 资助金额:
$ 94.17万 - 项目类别:
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