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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，是智力和智力障碍的主要原因发育障碍，估计每 700 名活产儿中就有 1 人患有 DS。多种同时发生的神经系统疾病的风险增加，包括自闭症、癫痫症和最近，越来越多的报告记录了患有阿尔茨海默病的人。表现出一种称为唐氏综合症回归障碍 (DSRD) 的病症，其中包括以下症状如紧张症、沉默症、人格解体、丧失进行日常生活活动的能力、幻觉、 DSRD 的病因尚不清楚，受影响的个体受到高度的影响。异质诊断检查和不同的治疗干预措施，包括精神科药物（例如劳拉西泮）、电休克疗法 (ECT) 和静脉注射免疫球蛋白 (IVIG)。显然需要对 DSRD 的病因学和不同疗法的相对疗效进行更多研究。我们在这里提出一个全面的临床研究计划，这不仅会增进我们对 DSRD 病因学，但这也将提供有关三种药物的相对安全性和有效性的重要信息重要的是，我们承认许多 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因此，我们建议完成三种潜在疗法的比较机制研究。 DSRD 疗法：苯二氮卓类劳拉西泮、IVIG 和 JAK 抑制剂托法替尼我们的具体目标是： 1. 为了确定劳拉西泮、IVIG 和托法替尼在 DSRD 中的相对安全性，我们将完成一份报告。劳拉西泮、IVIG 和托法替尼在 DSRD 患者中的随机、开放标签 II 期临床试验主要终点是安全性。 2. 使用评估的关键指标来比较劳拉西泮、IVIG 和托法替尼在 DSRD 中的疗效。对于患有 DSRD 的个体，一系列二级和三级终点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. 研究 DSRD 的潜在机制及其对治疗的反应。试验期间收集的受 DSRD 影响的个体的生物样本以及来自同伴的对照样本对 DS 个体进行积极的队列研究，我们将定义与 DSRD 诊断相关的生物特征以及每种治疗方式对这些生物特征的影响。这项 II 期试验的结果将为 DSRD 病因学和治疗提供急需的见解，为进一步研究 DSRD 铺平道路。未来更大规模试验的道路，以满足 DS 社区未满足的需求。