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

项目1：在结核病患者中检测ASD和ID的生物标志物和标记物 硬化症 总结 目前对自闭症谱系障碍（ASD）和智力残疾（ID）的治疗可以减轻一些 症状，但局限于没有一种机制性地靶向这些病症的潜在分子基础。 多发性硬化症（TSC）是一种遗传性疾病，具有ASD和ID的高发病率。 雷帕霉素（mTOR）途径机制靶点现在被批准用于TSC的多种临床表现， 包括室管膜下巨细胞星形细胞瘤（SEGA），肾血管平滑肌脂肪瘤（AML）， 淋巴管平滑肌瘤病（LAM）和癫痫。开发mTOR抑制剂和下一代治疗方法 对于TSC中的ASD和ID，迫切需要更好地表征神经发育表型， 开发预测ASD/ID风险、严重程度和治疗反应的合适生物标志物。使用一个前瞻性的， 纵向，多中心设计，我们将（1）在一个大型队列中描述ASD和ID的表型， 在一项前瞻性、多中心纵向设计中，对儿童和成人TSC患者进行研究;（2）识别 与TSC中的ASD和ID相关的突触功能和连接性的电生理学生物标志物;以及 (3)评估TAND检查表作为TSC特异性研究工具的适用性，以评估临床- 在未来的ASD和ID临床试验中获得有意义的结果。这些目标的实现将提供机械的 深入了解导致TSC中ASD和ID发展的潜在病理过程， 在未来的临床试验中使用mTOR抑制剂和下一代治疗方法进行靶向治疗。

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.