JAK Inhibition in Down Syndrome

唐氏综合症中的 JAK 抑制

基本信息

批准号：
10724473
负责人：
Joaquin M. Espinosa
金额：
$ 53.67万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724473
关键词：
Administrative Supplement Adult Affect Age Alopecia Areata Alzheimer&apos s Disease Atherosclerosis Atopic Dermatitis Autoantibodies Autoimmune Diseases Automobile Driving Award Blood specimen Brain Celiac Disease Chromosome 21 Chronic Clinical Clinical Management Clinical Trials Cognition Congenital Heart Defects Craniofacial Abnormalities Data Dermatologist Development Developmental Delay Disorders Dimensions Disease Down Syndrome Epilepsy Exhibits Funding Future General Population Grant Health Hidradenitis Suppurativa Human Chromosomes Hyperactivity Hypersensitivity Hypertension Immune Immune System Diseases Immune system Impaired cognition Individual Inflammatory Interferon Activation Interferon Receptor Interferons JAK1 gene Kynurenine Leukocytes Link Live Birth Longevity Malignant Neoplasms Measures Mediating National Institute of Arthritis, and Musculoskeletal, and Skin Diseases Parents Participant Pathology Pathway interactions Persons Pharmaceutical Preparations Phase II Clinical Trials Phenotype Population Prevalence Production Psoriasis Quality of life Reporting Research Risk Safety Signal Transduction Site Skin Solid Testing Therapeutic Time Transcriptional Activation Travel Tryptophan Viral Respiratory Tract Infection Vitiligo Whole Blood adverse event monitoring arm autism spectrum disorder autoimmune thyroid disease autoinflammatory cell type cognitive function cohort cost cytokine design experience geographic barrier immunomodulatory strategy improved inhibitor leukemia nervous system disorder neuroinflammation neurotoxic open label pharmacologic primary endpoint recruit response safety assessment safety testing secondary endpoint social implication transcriptome treatment arm

项目摘要

PROJECT SUMMARY/ABSTRACT. This is a proposal for an administrative supplement for an active clinical trial award testing the safety and efficacy of a JAK inhibitor to decrease the burden of autoimmune conditions in Down syndrome. This supplement would fund an approved extension arm for select participants as well as travel expenses to facilitate inclusion of remote and diverse participants. The Specific Aims of the parent award have not changed. Trisomy 21 (T21) causes a different disease spectrum in people with Down syndrome (DS), protecting these individuals from some conditions, while strongly predisposing them to others. For example, >50% of adults with T21 are affected by one or more autoimmune conditions, including a wide range of immune skin conditions. The mechanisms driving this different disease spectrum are poorly understood, which creates a challenge in the clinical management of DS. Our team demonstrated that T21 causes consistent activation of the interferon (IFN) response across diverse cell types, which is likely due to the fact that four of the six IFN receptors are encoded on chr21. Therefore, we hypothesize that hyperactivation of IFN signaling drives immune dysregulation and various pathologies in DS, and that pharmacological inhibition of IFN signaling could have multidimensional therapeutic benefits in this population. Accordingly, we propose here to complete a first- in-kind clinical trial for a JAK inhibitor in DS. Our Specific Aims are: 1. To define the safety profile of JAK inhibition in people with Down syndrome. We will perform an open- label Phase II clinical trial for Tofacitinib, a JAK1/3 inhibitor, in people with DS and an active immune skin condition, with the main primary endpoint being the assessment of safety. 2. To determine the impact of JAK inhibition on the immune dysregulation caused by trisomy 21. Using blood samples collected during the trial, we will define the impact of JAK inhibition on a) IFN scores derived from the transcriptome of white blood cells, b) circulating levels of inflammatory cytokines elevated in people with DS, c) levels of neurotoxic metabolites in the IFN-inducible kynurenine pathway, and d) levels of key autoantibodies. 3. To define the impact of JAK inhibition on immune skin conditions in Down syndrome. Using proven metrics currently employed in clinical trials of JAK inhibitors for immune skin conditions, our main secondary endpoint will be to determine whether JAK inhibition reduces skin pathology in DS. 4. To characterize the impact of JAK inhibition on cognition and quality of life in Down syndrome. Using a battery of tests to evaluate cognition in DS, we will explore the impact of JAK inhibition on diverse cognitive functions. The approved extension arm will enable a more thorough assessment of the potential therapeutic benefits of JAK inhibition, provide additional data points, and also document the stability of changes observed.

项目摘要/摘要。这是一项针对测试安全性和有效性的积极临床试验奖励的行政补充提案 JAK 抑制剂可减轻唐氏综合症自身免疫性疾病的负担。这个补充会为选定的参与者提供经批准的扩展机构以及差旅费，以促进远程教育的纳入以及多元化的参与者。家长奖的具体目标没有改变。 21 三体 (T21) 会导致唐氏综合症 (DS) 患者出现不同的疾病谱，从而保护这些患者个体会受到某些条件的影响，同时又会强烈地倾向于其他条件。例如，>50% 的成年人患有 T21 受到一种或多种自身免疫性疾病的影响，包括多种免疫性皮肤病。这人们对驱动这种不同疾病谱的机制知之甚少，这给研究带来了挑战 DS 的临床管理。我们的团队证明 T21 会导致干扰素 (IFN) 持续激活跨不同细胞类型的反应，这可能是由于编码了六种 IFN 受体中的四种在第 21 章。因此，我们假设 IFN 信号的过度激活会导致免疫失调和 DS 中的各种病理学，并且药物抑制 IFN 信号传导可能具有该人群的多维治疗益处。因此，我们在此建议完成第一个- JAK 抑制剂治疗 DS 的实物临床试验。我们的具体目标是： 1. 确定 JAK 抑制对唐氏综合症患者的安全性。我们将进行一次公开的标签 Tofacitinib（一种 JAK1/3 抑制剂）针对 DS 和免疫活性皮肤患者的 II 期临床试验条件，主要终点是安全性评估。 2. 确定 JAK 抑制对 21 三体引起的免疫失调的影响。在试验期间收集的血液样本中，我们将定义 JAK 抑制对 a) IFN 评分的影响白细胞转录组，b) DS 患者循环炎性细胞因子水平升高， c) IFN 诱导犬尿氨酸途径中神经毒性代谢物的水平，以及 d) 关键自身抗体的水平。 3. 确定 JAK 抑制对唐氏综合症皮肤免疫状况的影响。使用经过验证的目前用于治疗免疫性皮肤病的 JAK 抑制剂临床试验中使用的指标，我们的主要次要指标终点是确定 JAK 抑制是否会减轻 DS 中的皮肤病理。 4. 表征 JAK 抑制对唐氏综合症患者认知和生活质量的影响。使用通过一系列评估 DS 认知的测试，我们将探讨 JAK 抑制对不同认知的影响功能。批准的延长臂将能够更全面地评估潜在的治疗益处 JAK 抑制，提供额外的数据点，并记录观察到的变化的稳定性。