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：
10675475
负责人：
Adeline Lucie Vanderver
金额：
$ 12.49万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675475
关键词：
Address Advocacy Affect Age of Onset Anemia Assessment tool Autoimmune Hepatitis Biological Biological Markers Cardiomyopathies Categories 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 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 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 clinical outcome assessment clinical outcome measures clinical predictors clinical trial readiness cohort data integration design diaries disability disease natural history evidence base functional outcomes genetic signature improved industry partner inhibitor instrument kinase inhibitor leukodystrophy novel novel marker novel therapeutics outcome prediction overexpression patient population prospective pseudotoxoplasmosis syndrome rare genetic disorder systemic inflammatory response 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 Aicardi Goutières 综合征 (AGS) 是一种罕见的干扰素 (IFN) 产生过多的遗传性疾病，导致大多数受 AGS 影响的人患有严重的全身性炎症损伤和潜在的严重残疾。表现出一定程度的神经功能障碍，从轻度痉挛性截瘫到严重的全身性瘫痪此外，干扰素过度表达会导致全身症状和复发。无菌性发热伴严重、慢性烦躁的 AGS 治疗试验受到不同患者的限制。人口和缺乏针对特定疾病的结果措施。在具体目标 1 中，我们将在呈现时描述临床上不同的 AGS 亚组并评估我们预计基于统计相关性来识别队列。最能预测临床轨迹和结果的疾病特征。在具体目标 2 中，我们将定义一种新颖的 AGS 评级量表来评估纵向变化。在规定的时间点应用特定疾病的临床评级量表将与疾病更紧密地相关与每日症状日记进展和传统临床结果评估工具获得的结果进行比较在项目1中。在具体目标 3 中，我们将探讨前瞻性生物标志物、干扰素信号基因之间的比例 (ISG) 表达和临床结果。这些目标的预期成果是开发 AGS 临床试验准备工具。识别临床上不同的 AGS 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，并在这种情况下立即使用。