Improved clinical and biologic outcome measures in Aicardi Goutieres Syndrome

改善 Aicardi Goutieres 综合征的临床和生物学结果测量

基本信息

批准号：
10023212
负责人：
Adeline Lucie Vanderver
金额：
$ 12.16万
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：
2019-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023212
关键词：
Address Advocacy Affect Age of Onset Anemia Assessment tool Autoimmune Hepatitis Biological Biological Markers Cardiomyopathies Chronic Clinical Clinical Data Clinical Trials Clinical Trials Design Clinical Trials Network Collaborations Communities Companions Data Data Collection Development Developmental Delay Disorders Disease Disease Progression Endocrine System Diseases Enrollment Ensure Exhibits Fever Future Gene Expression Genes Genotype Goals Heterogeneity Impairment Individual Inflammation Inflammatory Injury Interferons Janus kinase Kidney Lead Measures Modeling Myopathy Natural History Neurologic Organ Outcome Outcome Assessment Outcome Measure Outcome Study Pain Patient Outcomes Assessments Patients Phenotype Pilot Projects Population Production Proxy Pulmonary Hypertension Rare Diseases Readiness Recording of previous events Recurrence Reporting Reverse Transcriptase Inhibitors Severities Severity of illness Signal Transduction Skin Spastic Paraparesis Statistical Models Subgroup Symptoms Testing Therapeutic Therapeutic Intervention Therapeutic Trials Thrombocytopenia Time Treatment Efficacy Variant base clinical predictors cohort data integration design diaries disability disease natural history evidence base functional outcomes genetic signature improved industry partner inhibitor/antagonist instrument kinase inhibitor leukodystrophy novel novel marker novel therapeutics outcome prediction overexpression patient population prospective pseudotoxoplasmosis syndrome rare genetic disorder tool tool development treatment response

项目摘要

ABSTRACT Aicardi Goutières Syndrome (AGS) is a rare genetic disorder of excessive interferon (IFN) production, resulting in severe, systemic inflammatory injury and potentially profound disabilities. Most individuals affected by AGS exhibit some degree of neurologic impairment, ranging from mild spastic paraparesis to severe global developmental delay. Additionally, interferon overexpression results in systemic manifestations and recurrent aseptic fevers with severe, chronic irritability. AGS therapeutic trials are limited by heterogeneous patient populations and the lack of disease-specific outcome measures. In Specific Aim 1, we will characterize clinically distinct AGS subgroups at the time of presentation and assess correlation with longitudinal history. We anticipate the identification of cohorts based on statistically relevant disease features that best predict clinical trajectory and outcome. In Specific Aim 2, we will define a novel AGS rating scale to assess longitudinal change. We hypothesize that application of a disease-specific clinical rating scale at defined time points will more closely correlate with disease progression compared to a daily symptom diary and traditional clinical outcome assessment tool results obtained in Project 1. In Specific Aim 3, we will explore the proportionality between a prospective biomarker, interferon signaling gene (ISG) expression, and clinical outcomes. The expected outcome of these aims is the development of tools for clinical trial readiness in AGS. We will identify clinically distinct subgroups of AGS, design an AGS-specific clinical rating scale, and explore the relationship of ISGs to clinical disease. It is expected that the development of these tools will facilitate clinical trial design, with immediate utilization in this setting.

抽象的 AicardiGoutières综合征（AGS）是一种过量干扰（IFN）产生的罕见遗传疾病，由此产生在严重的全身性炎症性损伤和潜在的严重疾病中。受AGS影响的大多数人表现出一定程度的神经系统障碍，范围从轻度痉挛性瘫痪到严重的全局发展延迟。此外，干扰素的过表达导致全身表现和经常性怀疑论的发烧，严重，慢性易怒。 AGS治疗试验受异构患者的限制人群和缺乏特定疾病的结局指标。在特定目标1中，我们将在演示和评估时表征临床上不同的AG子组与纵向历史相关。我们预计基于统计相关的人群可以识别队列最能预测临床轨迹和预后的疾病特征。在特定目标2中，我们将定义一个新颖的AG评级量表来评估纵向变化。我们假设这一点在定义的时间点上应用特异性临床评级量表将与疾病更紧密相关与每日症状日记和传统临床结果评估工具相比，进展在项目1中。在特定的目标3中，我们将探索前瞻性生物标志物干扰素信号基因之间的比例（ISG）表达和临床结果。这些目标的预期结果是开发AGS临床试验阅读工具。我们将确定AGS的临床上不同的亚组，设计AGS特定的临床评级量表，并探索 ISG与临床疾病的关系。预计这些工具的开发将有助于临床试验设计，在这种情况下立即利用。