JAK Inhibition in Down Syndrome

项目总结。 21三体(T21)导致唐氏综合征(DS)患者不同的疾病谱，保护这些 一些人患上了某些疾病，但却极易感染其他疾病。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。 不幸的是，驱动这种不同疾病谱的机制尚不清楚，这造成了一种 DS临床管理中的挑战。我们最近发现，T21导致持续的激活 不同细胞类型的干扰素反应，这可能是由于六种干扰素受体中的四种 编码在chr21上。因此，T21细胞对干扰素刺激高度敏感，表现出高度激活的 JAK/STAT信号转导，并过度表达干扰素刺激的基因。此外，数十种炎性细胞因子 在DS患者中是调节失调的，而T21通过干扰素-2驱动强神经毒性代谢物的产生。 诱导型犬尿氨酸途径。因此，我们假设干扰素信号的过度激活驱动 DS免疫失调与多种病理机制及干扰素的药理抑制 在这一人群中，信号可能具有多方面的治疗益处。因此，我们建议 在这里完成一项针对DS中JAK抑制剂的首个同类临床试验。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 与自身免疫性甲状腺疾病和乳糜泻有关，这是DS中两种常见的共生疾病。 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。皮肤病理减少也可能影响整体的健康和享受，以及 社会影响，这将通过生活质量评估来衡量。

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.