JAK Inhibition in Down Syndrome

唐氏综合症中的 JAK 抑制

• 批准号: 10512841
• 负责人: Joaquin M. Espinosa
• 金额: $ 110.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10512841
• 关键词: Adult; Affect; Age; Alopecia Areata; Alzheimer' s Disease; Atopic Dermatitis; Autoantibodies; Autoimmune Diseases; Automobile Driving; Blood specimen; Brain; Celiac Disease; Cells; Chronic; Clinical; Clinical Management; Clinical Trials; Cognition; Dermatologist; Development; 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; Pharmacology; Phase II Clinical Trials; Phosphotransferases; Plasma; Polycythemia Vera; Population; Process; Production; Proteomics; Psoriasis; Psoriatic Arthritis; Quality of life; Quality-of-Life Assessment; 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; phase III trial; prevent; primary endpoint; receptor; recruit; response; safety assessment; secondary endpoint; side effect; social implication; transcriptome

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）在唐氏综合征（DS）患者中引起不同的疾病谱， 一些人从某些疾病，而强烈倾向于他们对其他人。例如，>50%的成年人 T21受一种或多种自身免疫性疾病的影响，包括广泛的免疫性皮肤病。 不幸的是，驱动这种不同疾病谱的机制知之甚少，这就造成了一个 DS临床管理面临挑战。我们最近发现T21会导致大脑中 干扰素（IFN）反应跨越不同的细胞类型，这可能是由于事实上，四个六个IFN受体， 编码在chr 21上。因此，T21细胞对IFN刺激高度敏感，显示出IFN-γ的过度活化。 JAK/STAT信号传导，并过表达IFN刺激基因。此外，许多炎症细胞因子 在DS患者中失调，T21通过IFN-γ驱动强效神经毒性代谢产物的产生。 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了 DS中免疫失调和各种病理学以及IFN的药理学抑制 信号传导在这一人群中可能具有多方面的治疗益处。因此，我们建议 在这里完成JAK抑制剂在DS中的首次临床试验。我们的具体目标是： 1.确定JAK抑制剂在唐氏综合征患者中的安全性特征。我们将执行一个开放的- JAK 1/3抑制剂托法替尼在DS和活性免疫皮肤患者中的标签II期临床试验 条件，主要的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。使用 在试验期间收集的血液样品中，我们将定义JAK抑制对a）源自以下的IFN评分的影响： 白色血细胞的转录组，B）DS患者中炎性细胞因子的循环水平升高， c）IFN诱导型犬尿氨酸途径中神经毒性代谢物的水平，和 参与自身免疫性甲状腺疾病和乳糜泻，这是DS中两种常见的并发症。 3.明确JAK抑制对唐氏综合征患者免疫皮肤状况的影响。通过使用行之有效的 目前用于免疫性皮肤病JAK抑制剂临床试验的指标，我们的主要次要指标 终点将是确定JAK抑制是否减少DS中的皮肤病理学。 4.描述JAK抑制对唐氏综合征患者认知和生活质量的影响。使用 一组测试来评估DS中的认知，我们将探讨JAK抑制对不同认知功能的影响。 功能协调发展的减少皮肤病理也可能影响整体感知的健康和享受，以及具有 社会影响，这将通过生活质量评估来衡量。