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:10519053
- 负责人:
- 金额:$ 36.9万
- 依托单位:
- 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:
- 关键词:Activities of Daily LivingAffectAggressive behaviorAlzheimer&aposs DiseaseAmyloid beta-Protein PrecursorAutoantibodiesAutoimmune DiseasesBenzodiazepinesBiological MarkersCaregiversCatatoniaCerebrospinal FluidChromosome 21Clinical ResearchClinical TrialsCognitionCohort StudiesCommunitiesCompanionsDataDelusionsDepersonalizationDevelopmentDiagnosisDiagnosticDiseaseDown SyndromeElectroconvulsive TherapyElectroencephalogramEpilepsyEtiologyEvaluationFutureGene ProteinsGeneral PopulationGenetic DiseasesHallucinationsHealthHomeostasisHyperactivityImmuneImmunologyImmunotherapyIndividualIntellectual functioning disabilityInterferon ActivationInterferonsInterventionIntravenous ImmunoglobulinsInvestigationInvestigational TherapiesLanguageLinkLive BirthLorazepamMagnetic Resonance ImagingMeasurementMedicalMedicineModalityMonitorMotorMovementMutismNerve DegenerationNeuraxisNeurologicNeurologyParticipantPharmaceutical PreparationsPhase II Clinical TrialsPlasmaPrevalencePsychiatryQuality of lifeRandomizedReportingResearchRiskRoleSafetySamplingSignal PathwaySignal TransductionSleepSpeechSymptomsTherapeuticTherapeutic InterventionUnited StatesWorkautism spectrum disorderbiosignaturecell typecirculating biomarkerscomparativecomparative efficacycongenital heart disorderfunctional declineinflammatory markerinhibitorinsightleukemiamedication administrationmembermultidisciplinaryneuroimagingneuroinflammationneuropsychiatryneurotoxicopen labelphase II trialprimary endpointprogramsproteomic signatureresponsetreatment armtreatment durationtreatment 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。
唐氏综合征(DS),由21三体(T21)引起的遗传疾病,是智力和
发育残疾,估计患病率为每700名活产婴儿中有1名。个人与DS显示
增加了许多并发神经系统疾病的风险,包括自闭症、癫痫发作和
阿尔茨海默病(AD)。最近,越来越多的报告记录了患有DS的个体
显示一种被称为唐氏综合症回归障碍(DSRD)的疾病,其中包括以下症状,
如紧张症、缄默症、人格解体、丧失日常生活活动能力、幻觉,
妄想和攻击性DSRD的病因尚不清楚,受影响的个体受到高度的
异质性诊断检查和不同的治疗干预,包括精神病药物
(e.g.,劳拉西泮)、电休克治疗(ECT)和静脉注射免疫球蛋白(IVIG)。因此,我们认为,
显然需要对DSRD的病因学和不同疗法的相对功效进行额外的研究。
我们在这里提出了一个全面的临床研究计划,不仅将促进我们的理解,
DSRD病因,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
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-
基础疗法。因此,我们建议完成三个潜在的比较机制调查
DSRD疗法:苯二氮卓类药物劳拉西泮、IVIG和JAK抑制剂托法替尼。我们的具体目标是:
1.确定劳拉西泮、IVIG和托法替尼在DSRD中的相对安全性特征。我们将完成
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.比较劳拉西泮、IVIG和托法替尼治疗DSRD的疗效。使用关键指标进行评估
对于DSRD患者,一套次要和第三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.探讨DSRD的潜在机制及其对治疗的反应。使用
在试验期间从受DSRD影响的个体中采集的生物样本和从同伴中采集的对照样本
在DS患者的积极队列研究中,我们将定义与DSRD诊断相关的生物特征,
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病因和治疗提供急需的见解,为未来的研究铺平道路
为未来更大规模的试验铺平道路,以满足DS社区未满足的需求。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joaquin M. Espinosa其他文献
Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis
- DOI:
10.1016/j.jaci.2024.07.030 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:
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Sinéad Ryan;Louise Crowe;Sofía N. Almeida Cruz;Matthew D. Galbraith;Carol O’Brien;Juliet A. Hammer;Ronan Bergin;Shauna K. Kellett;Gary E. Markey;Taylor M. Benson;Olga Fagan;Joaquin M. Espinosa;Niall Conlon;Claire L. Donohoe;Susan McKiernan;Andrew E. Hogan;Eóin N. McNamee;Glenn T. Furuta;Calies Menard-Katcher;Joanne C. Masterson - 通讯作者:
Joanne C. Masterson
Sa1249: ASSESSMENT OF A GENETIC RISK SCORE FOR CELIAC DISEASE IN DOWN SYNDROME
- DOI:
10.1016/s0016-5085(22)60849-7 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:
- 作者:
Marisa G. Stahl;Jessica R. Shaw;Angela L. Rachubinski;Matthew D. Galbraith;Paul Norman;Sameer Chavan;Laura A. Leaton;Ronald J. Sokol;Edwin Liu;Joaquin M. Espinosa - 通讯作者:
Joaquin M. Espinosa
Joaquin M. Espinosa的其他文献
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{{ truncateString('Joaquin M. Espinosa', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 36.9万 - 项目类别:
A Pilot for Enhancing Support for a Federated Framework of Biospecimens for Down Syndrome Research via the INCLUDE Data Hub
通过 INCLUDE 数据中心加强对唐氏综合症研究生物样本联合框架的支持的试点
- 批准号:
10671310 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Interferon hyperactivity, COVID19, and Down syndrome
干扰素过度活跃、新冠肺炎 (COVID19) 和唐氏综合症
- 批准号:
10215951 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Understanding Down Syndrome as an Interferonopathy
将唐氏综合症理解为一种干扰素病
- 批准号:
9892863 - 财政年份:2019
- 资助金额:
$ 36.9万 - 项目类别:
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