: Clinical Outcomes in Aicardi Goutières Syndrome

Aicardi gouti<e:1>综合征（AGS）是一种干扰素（INF）产生过多的遗传性疾病。AGS是一种毁灭性的罕见疾病，发病率不到7000分之一，影响大脑、皮肤、骨髓和内脏器官。新的数据表明，使用Janus激酶（JAK）抑制剂进行IFN阻断治疗可能是有益的，并且在不久的将来可能会有进一步的抑制干扰素的治疗。自2017年2月开放baricitinib（一种JAK抑制剂（NCT01724580））的扩展准入使用计划以来，我们已经招募了超过18名个体，但缺乏适当的合格临床结局评估（COA）或生物标志物来评估效果。我们建议通过参与全球脑白质营养不良倡议临床试验网络（glia CTN）的多中心联盟来验证AGS中适当的结果测量和生物标志物。在这项提案中，我们将利用第一种方法来显示AGS的治疗前景，同时为未来的临床试验开发反应性结果测量和生物标志物。我们将验证AGS的临床结果评估工具（Aim 1），通过测试该人群中已建立的功能结果工具和患者报告的结果，包括他们对巴西替尼的反应性。我们将在多个测试中心进一步验证基于MRI的脑形态测量和弥散MRI指标的使用，以测量AGS患者的疾病进展（Aim 2），首先协调序列获取，然后确定脑萎缩和白质完整性与AGS发育结局的相关性。最后，我们将定义AGS中组织特异性干扰素生物标志物的使用背景（Aim 3），通过定义血液、皮肤中干扰素刺激基因（ISG）的表达测量与神经功能和皮肤病的临床测量之间的关系。拟议的研究将评估AGS临床试验的临床结果工具，在同情使用JAK抑制剂的背景下，使用患者特异性优先级和目标关键受影响器官。预计这些工具的发展将允许适当设计和实施使用JAK抑制剂和其他干扰素调节疗法的AGS临床试验。因此，我们希望该项目在罕见神经遗传疾病的临床试验准备方面具有迫切和未满足的需求，将被视为对PAR-18-534的响应，并在NINDS的任务范围内。

Aicardi Goutières Syndrome (AGS) is a heritable disorder of excessive interferon (INF) production. AGS is a devastating rare disease occurring in fewer than 1/7000 live births that affects brain, skin, bone marrow and visceral organs. New data suggest that treatment with IFN blockade using Janus Kinase (JAK) inhibitors may be beneficial and further therapies inhibiting interferons are likely in the near future. Since opening our expanded access use program for baricitinib, a JAK inhibitor (NCT01724580), in February 2017, we have enrolled more than eighteen individuals, but lack appropriate qualified clinical outcome assessments (COA) or biomarkers to assess effect. We propose to use our participation in the multicenter consortium the Global Leukodystrophy Initiative Clinical Trial Network –GLIA CTN- to validate appropriate outcome measures and biomarkers in AGS. In this proposal, we will leverage the first approach to show therapeutic promise in AGS to concomitantly develop responsive outcome measures and biomarkers for future clinical trials. We will validate clinical outcomes assessment tools in AGS (Aim 1) by testing established functional outcomes tools and patient reported outcomes in this population including their responsiveness to baricitinib. We will further validate use of MRI-based metrics of brain morphometry and diffusion MRI that measure disease progression in AGS patients (Aim 2) across multiple testing centers, first harmonizing sequence acquisition and then determining the correlation of brain atrophy and white matter integrity with developmental outcomes in AGS. Finally, we will define context of use for tissue specific interferon biomarkers in AGS (Aim 3), by defining the relationship between measures of expression of interferon stimulatory genes (ISG) in blood, skin and clinical measures of neurologic function and skin disease. The proposed research will evaluate clinical outcomes tools for AGS clinical trials using patient-specific priorities and target key affected organs in the context of compassionate use of JAK inhibitors. It is expected that the development of these tools will allow appropriate design and implementation of clinical trials in AGS using JAK inhibitors and other interferon modulating therapies. Thus, we hope that this project, with urgent and unmet need in clinical trial readiness in a rare neurogenetic disease, will be viewed as responsive to PAR-18-534 and within the NINDS mission.