Mechanistic investigation of therapies for Down Syndrome Regression Disorder

唐氏综合症回归障碍治疗的机制研究

• 批准号: 10701872
• 负责人: Joaquin M. Espinosa
• 金额: $ 117.64万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701872
• 关键词: Activities of Daily Living; Affect; Aggressive behavior; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Autoantibodies; Autoimmune Diseases; Benzodiazepines; Biological Markers; Caregivers; Catatonia; Central Nervous System; Cerebrospinal Fluid; Chromosome 21; Clinical Research; Clinical Trials; Cognition; Cohort Studies; Communities; Companions; Data; Delusions; Depersonalization; Development; Diagnosis; Diagnostic; Disease; Disparate; Down Syndrome; Electroconvulsive Therapy; Electroencephalography; Epilepsy; Etiology; Evaluation; Future; Gene Proteins; General Population; Genetic Diseases; Hallucinations; Health; Homeostasis; Hyperactivity; Immune; Immunology; Immunotherapy; Individual; Intellectual functioning disability; Interferon Activation; Interferons; Intervention; Intravenous Immunoglobulins; Investigation; Language; Link; Live Birth; Lorazepam; Magnetic Resonance Imaging; Measurement; Medical; Medicine; Modality; Monitor; Motor; Movement; Mutism; Nerve Degeneration; Neurologic; Neurology; Participant; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Prevalence; Psychiatry; Quality of life; Randomized; Reporting; Research; Risk; Role; Safety; Sampling; Signal Pathway; Signal Transduction; Sleep; Speech; Symptoms; Therapeutic; Therapeutic Intervention; United States; Work; autism spectrum disorder; biosignature; cell type; circulating biomarkers; comparative; comparative efficacy; congenital heart disorder; functional decline; improved; inflammatory marker; inhibitor; insight; leukemia; medication administration; member; multidisciplinary; neuroimaging; neuroinflammation; neuropsychiatry; neurotoxic; open label; phase II trial; primary endpoint; programs; proteomic signature; response; symptomatic improvement; treatment arm; treatment duration; treatment response

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.

项目摘要。 唐氏综合症（DS）是由21三体（T21）引起的遗传病，是智力和 发育障碍，估计患病率为700个活产。 DS显示的个人 增加了许多同时发生的神经系统疾病的风险，包括自闭症，癫痫发作和 阿尔茨海默氏病（AD）。最近，越来越多的报告记录了DS的个人 显示一种称为唐氏综合症回归障碍（DSRD）的疾病，其中包括此类符号 作为catatonia，mutism，非人格化，无法执行日常生活活动，幻觉的能力丧失， 妄想和侵略性。 DSRD的病因尚不清楚，受影响的个体受到高度的影响 异源诊断工作和不同的治疗干预措施，包括精神病药物 （例如Lorazepam），电击疗法（ECT）和静脉内免疫球蛋白（IVIG）。所以， 显然需要对DSRD病因和不同疗法的相对效率的进一步研究。 我们在这里提出了一项全面的临床研究计划，不仅会提高我们对 DSRD病因，但还将提供有关三个相对安全性和效率的重要信息 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）的失调，这些病例将受益于免疫 基于疗法。因此，我们建议完成三个潜力的比较机械研究 DSRD疗法：苯二氮卓劳拉西m，IVIG和JAK抑制剂Tofacitinib。我们的具体目的是： 1。定义DSRD中Lorazepam，Ivig和Tofacitinib的相对安全性。我们将完成一个 在患有DSRD的个体的Lorazepam，Ivig和Tofacitinib的随机，开放标签，II期临床试验 主要终点是安全。 2。比较DSRD中Lorazepam，Ivig和Tofacitinib的效率。使用关键指标进行评估 在患有DSRD的个体中，一套二级和第三级终点将评估整体的改进 神经健康健康，日常生活和生活质量以及特定领域的改进 Catatonia，运动和运动功能，语音，睡眠和认知。 3。研究DSRD的潜在机制及其对疗法的反应。使用 来自在试验期间收集的DSRD的个体的生物测量和对照样本的伴侣。 对DS个体的积极队列研究，我们将定义与DSRD诊断相关的生物签名和 每种治疗方式对这些生物签名的影响。 这次II阶段试验的结果将产生对DSRD病因和治疗的急需见解，并铺路 未来大型试验的道路，以满足DS社区未满足的需求。