JAK Inhibition in Down Syndrome

唐氏综合症中的 JAK 抑制

• 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
• 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' 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

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。 这是一项对有效临床试验奖进行安全性和有效性测试的行政补充建议。 应用JAK抑制剂减轻唐氏综合征患者自身免疫状况的负担。这份副刊将 为特定参与者批准的扩展分支提供资金，并支付差旅费用，以促进远程 和不同的参与者。家长奖的具体目标没有改变。 21三体(T21)导致唐氏综合征(DS)患者不同的疾病谱，保护这些 个人不受某些条件的影响，同时强烈倾向于其他人。例如，有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，包括广泛的免疫性皮肤疾病。这个 驱动这种不同疾病谱的机制尚不清楚，这在 DS的临床处理。我们的团队证明了T21导致干扰素(干扰素)的持续激活 跨不同细胞类型的反应，这可能是由于六种干扰素受体中的四种是编码的 在21号公路上。因此，我们假设干扰素信号的过度激活会导致免疫失调。 以及在DS中的各种病理机制，以及对干扰素信号的药物抑制可能有 在这一人群中的多维治疗益处。因此，我们建议在此完成第一个- 一种JAK抑制剂用于DS的实物临床试验。我们的具体目标是： 1.明确JAK抑制剂在唐氏综合征患者中的安全性。我们将表演一场公开赛- JAK1/3抑制剂tofacitinib在DS和免疫活性皮肤患者中的LABEL II期临床试验 条件，主要的主要终点是安全评估。 2.探讨JAK抑制对21三体所致免疫功能紊乱的影响。vbl.使用 在试验期间采集的血液样本，我们将确定JAK抑制对a)干扰素评分的影响 白血球转录组，b)DS患者循环中炎性细胞因子水平升高， C)干扰素诱导的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.明确JAK抑制对唐氏综合征患者皮肤免疫状况的影响。使用经验证的 目前JAK抑制剂用于免疫性皮肤状况的临床试验中使用的指标，我们的主要次要指标 终点将是确定JAK抑制是否减少DS患者的皮肤病理。 4.探讨JAK抑制对唐氏综合征患者认知和生活质量的影响。vbl.使用 一组评估DS认知的测试，我们将探索JAK抑制对不同认知的影响 功能。 批准的延长臂将使更彻底的评估潜在的治疗效益 JAK抑制，提供更多数据点，并记录观察到的变化的稳定性。