: Clinical Outcomes in Aicardi Goutières Syndrome

: Aicardi Goutières 综合征的临床结果

基本信息

批准号：
10459505
负责人：
Adeline Lucie Vanderver
金额：
$ 144.06万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459505
关键词：
Adaptive Behaviors Affect Aftercare Area Assessment tool Atrophic Biological Markers Blood Bone Marrow Brain Brain Injuries Caring Central Nervous System Diseases Child Clinical Clinical Trials Clinical Trials Network Clinical assessments Clinical/Radiologic Corpus striatum structure Custom Cutaneous Lupus Erythematosus Data Development Diffusion Diffusion Magnetic Resonance Imaging Disease Disease Marker Disease Outcome Disease Progression Enrollment Face Family Future Gene Expression Genes Genotype Hereditary Disease Immune Individual Interferons JAK1 gene Janus kinase Laboratories Laboratory Markers Leadership Learning Letters Link Live Birth Lupus MRI Scans Magnetic Resonance Imaging Measurement Measures Mission Motor National Institute of Neurological Disorders and Stroke Natural History Nervous System Physiology Observational Study Organ Outcome Outcome Assessment Outcome Measure Pathway interactions Patient Outcomes Assessments Patients Pharmaceutical Preparations Phenotype Population Positioning Attribute Production Property Rare Diseases Reporting Reproducibility Research Rheumatoid Arthritis Severities Severity of illness Signal Transduction Skin Standardization Symptoms Testing Therapeutic Time Tissues Visceral base brain magnetic resonance imaging cerebral atrophy clinical outcome assessment clinical outcome measures clinical trial implementation clinical trial readiness design diaries functional outcomes imaging approach imaging platform improved indexing inhibitor innovation interest kinase inhibitor leukodystrophy magnetic resonance imaging biomarker morphometry nervous system disorder neurogenetics neuroimaging novel therapeutics programs pseudotoxoplasmosis syndrome rare condition skin disorder tool tool development white matter

项目摘要

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.

AicardiGoutières综合征（AGS）是一种过多干扰（INF）生产的遗传障碍。 AGS是一种毁灭性的罕见疾病，发生在不到1/7000个活产的活产，会影响大脑，皮肤，骨髓和内脏器官。新数据表明，使用Janus激酶（JAK）抑制剂对IFN阻断的治疗可能是有益的，并且在不久的将来可能会进一步抑制干扰。自2017年2月开放了JAK抑制剂Baricitinib（NCT01724580）Bariticinib扩展的访问使用计划以来，我们已经招募了18个人，但缺乏合适的合格的临床结果评估（COA）或生物标志物来评估效果。我们建议利用我们参与多中心财团的全球白细胞营养不良计划临床试验网络 - GLIA CTN-以验证AGS中适当的结果指标和生物标志物。在此提案中，我们将利用第一种表现出AG中治疗诺言的方法，以同时制定响应良好的结果指标和生物标志物，以进行将来的临床试验。我们将通过测试已建立的功能结果工具和患者报告的该人群中的临床结果评估工具（AIM 1）验证临床结果评估工具（AIM 1），包括对Bariticinib的反应性。我们将进一步验证使用基于MRI的脑形态计量学和扩散MRI的指标，即在多个测试中心中测量AGS患者的疾病进展（AIM 2），首先协调序列采集，然后确定脑萎缩和白质完整性与年龄的发育效果的相关性。最后，我们将通过在神经系统功能和皮肤疾病的血液，皮肤和临床测量中定义测量干扰素刺激基因表达（ISG）的测量方法，来定义AGS中组织特异性干扰素生物标志物的使用背景。拟议的研究将使用特定于患者的优先级评估针对AGS临床试验的临床结果工具，并在同情使用JAK抑制剂的情况下针对关键影响器官。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AG中进行适当的设计和实施。这就是我们希望这个项目在罕见的神经遗传疾病中的临床试验准备情况下紧急和未满足的需求，将被视为对PAR-18-534和NINDS任务中的反应。