JAK Inhibition in Down Syndrome

唐氏综合症中的 JAK 抑制

基本信息

批准号：
10682481
负责人：
Joaquin M. Espinosa
金额：
$ 187.15万
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/10682481
关键词：
Adult Affect Age Alopecia Areata Alzheimer&apos s Disease Atopic Dermatitis Autoantibodies Autoimmune Diseases Automobile Driving Blood specimen Brain Celiac Disease Cells Chronic Clinical Clinical Management Clinical Trials Cognition Dermatologist Development Dimensions Disease Down Syndrome Exclusion Criteria Future Genes Health Hidradenitis Suppurativa Homeostasis Hyperactivity Hypersensitivity Immune Immune System Diseases Individual Inflammatory Insulin-Dependent Diabetes Mellitus Interferon Activation Interferon Receptor Interferons JAK1 gene Kynurenine Leukocytes Life Expectancy Link Malignant Neoplasms Measures Myelofibrosis Outcome Pathology Pathway interactions Persons Phase II Clinical Trials Phosphotransferases Plasma Polycythemia Vera Population Process Production Proteomics Psoriasis Psoriatic Arthritis Quality of Life Assessment Quality of life Reporting Rheumatoid Arthritis Role Safety Signal Pathway Signal Transduction Skin Solid Testing Therapeutic Transcriptional Activation Tryptophan Ulcerative Colitis Vitiligo adverse event monitoring autoimmune thyroid disease cell type cognitive function cytokine follow-up immunomodulatory strategy improved inhibitor metabolomics multidisciplinary nervous system disorder neuroinflammation neurotoxic novel open label overexpression pharmacologic phase III trial prevent primary endpoint recruit response safety assessment secondary endpoint side effect social implication transcriptome

项目摘要

PROJECT SUMMARY. Trisomy 21 (T21) causes a different disease spectrum in people with Down syndrome (DS), protecting these individuals from some diseases, 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. Unfortunately, the mechanisms driving this different disease spectrum are poorly understood, which creates a challenge in the clinical management of DS. We recently discovered 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. Accordingly, T21 cells are hypersensitive to IFN stimulation, display hyperactivation of JAK/STAT signaling, and overexpress IFN-Stimulated Genes. Furthermore, dozens of inflammatory cytokines are dysregulated in people with DS, and T21 drives production of potent neurotoxic metabolites via the IFN- inducible kynurenine pathway. 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 involved in autoimmune thyroid disease and celiac disease, two common co-occurring conditions in DS. 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. Decreased skin pathology may also affect overall perceived health and enjoyment, as well as have social implications, which will be measured by quality of life assessments.

项目摘要。 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患有某些疾病，同时又极易患上其他疾病。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。不幸的是，人们对驱动这种不同疾病谱的机制知之甚少，这造成了 DS 临床管理面临的挑战。我们最近发现 T21 会导致持续激活干扰素 (IFN) 跨不同细胞类型的反应，这可能是由于六种 IFN 受体中的四种在 chr21 上编码。因此，T21 细胞对 IFN 刺激高度敏感，表现出过度激活 JAK/STAT 信号传导，并过度表达 IFN 刺激的基因。此外，还有数十种炎症细胞因子 DS 患者体内的 T21 失调，T21 通过 IFN- 驱动强效神经毒性代谢物的产生诱导型犬尿氨酸途径。因此，我们假设 IFN 信号的过度激活驱动 DS 中的免疫失调和各种病理，以及 IFN 的药理学抑制信号传导可能对该人群产生多维的治疗益处。据此，我们建议在这里完成 JAK 抑制剂治疗 DS 的首次同类临床试验。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涉及自身免疫性甲状腺疾病和乳糜泻，这是 DS 中两种常见的并发疾病。 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。皮肤病理学的减少也可能影响整体健康和享受，以及社会影响，将通过生活质量评估来衡量。