: 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.

Aicardi Goutières 综合征 (AGS) 是一种干扰素 (INF) 产生过多的遗传性疾病，是一种毁灭性的罕见疾病，发生率不到 1/7000，会影响大脑、皮肤、骨髓和内脏器官。使用 Janus 激酶 (JAK) 抑制剂进行干扰素阻断可能是有益的，并且自从开放我们的扩大使用计划以来，在不久的将来可能会出现进一步的抑制干扰素的疗法。 baricitinib，一种 JAK 抑制剂（NCT01724580），在 2017 年 2 月，我们已经招募了超过 18 个人，但缺乏适当的合格临床结果评估（COA）或生物标志物来评估效果，我们建议利用我们参与的多中心联盟 Global Leukodystropy。倡议临床试验网络 – GLIA CTN – 验证 AGS 中适当的结果测量和生物标志物在本提案中，我们将利用第一种方法来展示 AGS 的治疗前景。同时开发用于未来临床试验的反应性结果测量和生物标志物，我们将通过测试已建立的功能结果工具和患者报告的结果（包括他们对巴瑞克替尼的反应）来验证 AGS 中的临床结果评估工具。基于 MRI 的脑形态测定和扩散 MRI 指标，可跨多个测试中心测量 AGS 患者的疾病进展（目标 2），首先协调序列采集，然后确定脑萎缩和白质完整性与发育的相关性最后，我们将通过定义血液、皮肤中干扰素刺激基因（ISG）的表达测量与神经功能和临床测量之间的关系来定义 AGS 中组织特异性干扰素生物标志物的使用背景（目标 3）。拟议的研究将使用患者特定的优先事项来评估 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受影响的器官。预计这些工具的开发将允许适当的设计和实施。临床的使用 JAK 抑制剂和其他干扰素调节疗法在 AGS 中进行的试验因此，我们希望该项目能够被视为对 PAR-18-534 做出反应并在 NINDS 范围内，该项目在罕见神经遗传疾病的临床试验准备中具有迫切且未满足的需求。使命。