Developing Biomarkers and Treatments for ASD and ID in Tuberous Sclerosis Complex

开发结节性硬化症 ASD 和 ID 的生物标志物和治疗方法

基本信息

批准号：
10242079
负责人：
Darcy Krueger
金额：
$ 36.23万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242079
关键词：
18 year old 21 year old 3 year old Adult Age Age-Years Assessment tool Auditory Evoked Potentials Behavior assessment Behavioral Behavioral Symptoms Biological Markers Centers of Research Excellence Child Childhood Clinical Clinical Research Clinical Treatment Clinical Trials Development Diffusion Magnetic Resonance Imaging Disability phenotype Disease Electroencephalography Electrophysiology (science)Enrollment Epilepsy Evoked Potentials FRAP1 gene Future Genetic Diseases Gold Image Impairment Individual Infant Intellectual functioning disability Life Longevity Lymphangioleiomyomatosis Measurement Measures Mendelian disorder Molecular Molecular Target Mutation Natural History Neurocognitive Outcome Outcome Assessment PTEN gene Participant Pathologic Processes Pathway interactions Patients Pediatric cohort Penetrance Phase Phelan-McDermid syndrome Phenotype Positioning Attribute Practice Management Rare Diseases Renal Angiomyolipoma Research Sensory Severities Signal Pathway Standardization Structure Subependymal Giant Cell Astrocytoma Surrogate Markers Symptoms Synapses Time Treatment outcome Tuberous sclerosis protein complex Visual Work autism spectrum disorder autistic children base clinical phenotype clinical practice clinical trial readiness cohort design disability risk inhibitor/antagonist insight longitudinal design molecular targeted therapies neurobehavioral neuronal circuit disruption neuropsychiatric disorder neuropsychiatric symptom next generation predictive marker prospective social standard measure synaptic function targeted treatment tool treatment response

项目摘要

PROJECT 1: DEVELOPING BIOMARKERS AND TREATMENTS FOR ASD AND ID IN TUBEROUS SCLEROSIS COMPLEX SUMMARY Current treatments for Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) can alleviate some symptoms but are limited in that none mechanistically target the underlying molecular basis for these conditions. Tuberous Sclerosis Complex (TSC) is a genetic disorder with high penetrance of ASD and ID. Inhibitors of the mechanistic target of rapamycin (mTOR) pathway are now approved for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), and epilepsy. To develop mTOR inhibitors and next-generation treatments for ASD and ID in TSC, there is critical need to better characterize the neurodevelopmental phenotype and to develop suitable biomarkers predictive of ASD/ID risk, severity, and treatment response. Using a prospective, longitudinal, multi-center design, we will (1) characterize the phenotype of ASD and ID in a large cohort of pediatric and adult patients with TSC in a prospective, multi-center longitudinal design; (2) identify electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and (3) evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically- meaningful outcomes in future ASD and ID clinical trials. Completion of these aims will provide mechanistic insight into the underlying pathological processes contributing to development of ASD and ID in TSC that can be targeted with mTOR inhibitors and next generation treatments in future clinical trials.

项目1：在块茎中开发ASD和ID的生物标志物和治疗硬化症复合物概括自闭症谱系障碍（ASD）和智力残疾（ID）的当前治疗方法可以缓解一些症状但受到限制，因为没有机械机械地针对这些条件的基本分子基础。结节性硬化症复合物（TSC）是一种遗传疾病，具有ASD和ID的高渗透率。抑制剂雷帕霉素（MTOR）途径的机理靶标现在已批准用于TSC的多种临床表现，包括亚依赖型巨型细胞星形细胞瘤（SEGA），肾血管肌瘤（AML），淋巴管肌瘤病（LAM）和癫痫。开发MTOR抑制剂和下一代治疗对于TSC中的ASD和ID，迫切需要更好地表征神经发育表型和开发适当的生物标志物可以预测ASD/ID风险，严重性和治疗反应。使用潜在的纵向，多中心设计，我们将（1）在大量队列中表征ASD和ID的表型在预期的多中心纵向设计中患有TSC的小儿和成年患者；（2）识别与TSC中ASD和ID相关的突触功能和连通性的电生理生物标志物；和（3）评估TAND清单作为TSC特异性研究工具的适用性，用于评估临床未来的ASD和ID临床试验中有意义的结果。这些目标的完成将提供机械深入了解导致TSC中ASD和ID发展的基本病理过程在将来的临床试验中，以MTOR抑制剂和下一代疗法为目标。