JAK Inhibition in Down Syndrome

项目总结/摘要。 这是一份关于积极临床试验奖励的行政补充提案，旨在测试安全性和有效性 JAK抑制剂，以减少唐氏综合征的自身免疫性疾病的负担。这一补充将 为选定参与者的一个核准的扩展分支提供资金，并支付差旅费， 不同的参与者。主奖项的具体目标没有改变。 21三体（T21）在唐氏综合征（DS）患者中引起不同的疾病谱， 个人从某些条件，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。的 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导致干扰素（IFN）的持续激活， 这可能是由于六种IFN受体中的四种被编码， 关于chr 21因此，我们假设IFN信号的过度激活驱动免疫失调 以及DS中的各种病理学，以及IFN信号传导的药理学抑制可能具有 多方面的治疗益处。因此，我们在此建议完成第一个- JAK抑制剂在DS中的实物临床试验。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d）关键自身抗体的水平。 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 获批的延伸臂将能够更全面地评估 JAK抑制，提供额外的数据点，并记录观察到的变化的稳定性。

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.