: Clinical Outcomes in Aicardi Goutières Syndrome

Aicardi Gtières综合征(AGS)是一种干扰素(INF)分泌过多的遗传性疾病。AGS是一种毁灭性的罕见疾病，发生在不到7000名活产婴儿中，影响到大脑、皮肤、骨髓和内脏器官。新的数据表明，使用Janus Kinase(JAK)抑制剂进行干扰素阻断治疗可能是有益的，在不久的将来可能会有进一步的治疗方法来抑制干扰素。自2017年2月启动JAK抑制剂巴利替尼(NCT01724580)的扩大使用计划以来，我们已经招募了18名以上的患者，但缺乏适当的合格临床结果评估(COA)或生物标记物来评估疗效。我们建议利用我们在多中心联盟全球白质营养不良临床试验网络(GILA CTN)中的参与来验证AGS中适当的结果测量和生物标记物。在这项提案中，我们将利用第一种方法在AGS中显示治疗前景，同时为未来的临床试验开发反应灵敏的结果指标和生物标记物。我们将通过在这一人群中测试已建立的功能结果工具和患者报告的结果，包括他们对巴利替尼的反应性，来验证AGS(AIM 1)中的临床结果评估工具。我们将进一步验证基于MRI的脑形态测量和扩散MRI指标的使用，这些指标跨多个测试中心测量AGS患者(AIM 2)的疾病进展，首先协调序列采集，然后确定脑萎缩和白质完整性与AGS患者发育结果的相关性。最后，我们将通过定义血液和皮肤中干扰素刺激基因(ISG)的表达指标与神经功能和皮肤病的临床指标之间的关系，来定义组织特异性干扰素生物标记物在AGS(目标3)中的使用范围。拟议的研究将评估AGS临床试验的临床结果工具，使用患者特定的优先事项，并在同情地使用JAK抑制剂的背景下针对关键受影响的器官。预计这些工具的开发将允许使用JAK抑制剂和其他干扰素调节疗法在AGS中进行适当的临床试验设计和实施。因此，我们希望这个项目，在一种罕见的神经遗传疾病的临床试验准备方面有迫切和未得到满足的需求，将被视为对PAR-18-534和NINDS任务的响应。

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.