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

项目1：开发治疗结节ASD和ID的生物标记物和治疗方法 硬化症复合体 摘要 目前对自闭症谱系障碍(ASD)和智能障碍(ID)的治疗方法可以缓解一些 症状，但有限的是，没有一个机械地针对这些疾病的潜在分子基础。 结节性硬化症(TSC)是一种遗传性疾病，具有ASD和ID的高外显性。 雷帕霉素途径的机制靶点(MTOR)现已被证实可用于TSC的多种临床表现， 包括室管膜下巨细胞星形细胞瘤(SEGA)、肾血管肌脂肪瘤(AML)、 淋巴管肌瘤病(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，迫切需要更好地描述神经发育表型和 开发预测ASD/ID风险、严重程度和治疗反应的合适生物标记物。使用一个预期的， 纵向、多中心设计，我们将(1)描述ASD和ID的表型。 儿童和成人TSC前瞻性、多中心纵向设计；(2)确定 TSC中与ASD和ID相关的突触功能和连接性的电生理生物标志物；以及 (3)评估Tand Checklist作为TSC特定研究工具在临床评估中的适用性。 在未来的ASD和ID临床试验中取得有意义的结果。完成这些目标将提供机械性 洞察导致TSC中ASD和ID发生的潜在病理过程 在未来的临床试验中以mTOR抑制剂和下一代治疗为靶点。

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.