Mechanistic investigation of therapies for Down Syndrome Regression Disorder

项目总结。 唐氏综合征(DS)是由21三体(T21)引起的遗传疾病，是导致智力和 发育障碍，估计患病率为每700名活产儿中有1名。具有DS显示器的个人 增加多种神经系统疾病的风险，包括自闭症、癫痫障碍和 阿尔茨海默病(AD)。最近，越来越多的报告记录了患有DS的个人 表现出一种被称为唐氏综合症回归障碍(DSRD)的疾病，包括以下症状 如紧张症，沉默，人格解体，丧失日常生活能力，幻觉， 妄想症和攻击性。DSRD的病因尚不清楚，受影响的人受到高度 不同的诊断工作和不同的治疗干预措施，包括精神药物 (例如，洛拉西潘)、电休克治疗(ECT)和静脉注射免疫球蛋白(IVIG)。因此， 显然需要对DSRD的病因和不同疗法的相对疗效进行更多的研究。 我们在这里提出了一个全面的临床研究计划，不仅将增进我们对 DSRD病因学，但这也将提供关于三种药物相对安全性和有效性的重要信息 不同的治疗方法。重要的是，我们假设许多DSRD病例是由免疫驱动的 影响中枢神经系统(CNS)的调节失调，这些病例将受益于免疫- 以治疗为基础。因此，我们建议完成对三种潜能的比较机制的调查。 DSRD的治疗方法：苯二氮卓类、洛拉西潘、静脉注射丙种球蛋白和JAK抑制剂tofacitinib。我们的具体目标是： 1.确定洛拉西潘、静脉注射丙种球蛋白和托法替尼在DSRD中的相对安全性。我们将完成一个 洛拉西潘、静脉注射丙种球蛋白和托法替尼治疗DSRD患者的随机开放标签II期临床试验 主要终点是安全。 2.比较洛拉西潘、丙种球蛋白和托法替尼治疗DSRD的疗效。使用关键指标进行评估 对于患有DSRD的个人，一套第二和第三终端将评估总体改善情况 神经健康、日常生活活动和生活质量，以及特定领域的改善 紧张症、运动和运动功能、言语、睡眠和认知。 3.探讨DSRD的潜在机制及其对治疗的反应。vbl.使用 在试验期间收集的受DSRD影响的个体的生物旋毛虫和来自同伴的对照样本 DS患者的积极队列研究，我们将定义与DSRD诊断和 每种处理方式对这些生物特征的影响。 这项II期试验的结果将对DSRD的病因和治疗产生迫切需要的见解，为 为未来更大规模的试验铺平道路，以满足DS社区中未得到满足的需求。

PROJECT SUMMARY. Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is a leading cause of intellectual and developmental disability, with an estimated prevalence of 1 in 700 live births. Individuals with DS display increased risk of numerous co-occurring neurological conditions including autism, seizure disorders, and Alzheimer’s disease (AD). Recently, an increasing number of reports have documented individuals with DS displaying a condition known as Down Syndrome Regression Disorder (DSRD), which include symptoms such as catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression. The etiology of DSRD is unclear, with affected individuals being subjected to highly heterogenous diagnostic work ups and disparate therapeutic interventions, including psychiatric medications (e.g., Lorazepam), electroconvulsive therapy (ECT), and intravenous immunoglobulin (IVIG). Therefore, additional research into the etiology of DSRD and the relative efficacy of different therapies is clearly needed. We propose here a comprehensive clinical research program that will not only advance our understanding of DSRD etiology, but which would also provide important information about the relative safety and efficacy of three different therapeutic approaches. Importantly, we hypothesize that many DSRD cases are driven by immune dysregulation affecting the central nervous system (CNS) and that these cases will benefit from immune- based therapies. Therefore, we propose to complete a comparative mechanistic investigation of three potential DSRD therapies: the benzodiazepine Lorazepam, IVIG, and the JAK inhibitor Tofacitinib. Our Specific Aims are: 1. To define the relative safety profile of Lorazepam, IVIG, and Tofacitinib in DSRD. We will complete a randomized, open-label, Phase II clinical trial for Lorazepam, IVIG, and Tofacitinib in individuals with DSRD with the primary endpoint being safety. 2. To compare the efficacy of Lorazepam, IVIG, and Tofacitinib in DSRD. Using key metrics for the evaluation of individuals with DSRD, a suite of secondary and tertiary endpoints will assess improvements in overall neurological health, activities of daily living, and quality of life, as well as domain-specific improvements in catatonia, movement and motor function, speech, sleep, and cognition. 3. To investigate potential mechanisms underlying DSRD and its response to therapies. Using biospecimens from individuals affected by DSRD collected during the trial and control samples from a companion active cohort study of individuals with DS, we will define biosignatures associated with DSRD diagnosis and the impact of each treatment modality on these biosignatures. Results from this phase II trial will generate much needed insights into DSRD etiology and treatment, paving the road for future larger trials to fulfill an unmet need in the DS community.