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

• 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
• 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

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.

摘要 Aicardi Gtières综合征(AGS)是一种罕见的干扰素(干扰素)过度产生的遗传性疾病，导致 严重的全身性炎症性损伤和潜在的严重残疾。大多数受AGS影响的个人 表现出一定程度的神经损害，从轻微的痉挛瘫痪到严重的全身性瘫痪 发育迟缓。此外，干扰素过度表达会导致全身症状和复发 无菌发热，伴有严重的慢性过敏性。AGS治疗试验受到异种患者的限制 人口和缺乏针对疾病的结果衡量标准。 在特定的目标1中，我们将在陈述和评估时描述临床上不同的AGS亚群的特征 与纵向历史的相关性。我们预计基于统计相关性的队列识别 最能预测临床轨迹和结果的疾病特征。 在具体目标2中，我们将定义一种新的AGS评级标准来评估纵向变化。我们假设 在确定的时间点应用疾病特异性临床评定量表将与疾病更密切地相关 与每日症状日记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。 在特定的目标3中，我们将探索一个潜在的生物标志物干扰素信号基因之间的比例关系。 (ISG)表达和临床结果。 这些目标的预期结果是开发用于AGS临床试验准备的工具。我们会 确定临床上不同的AGS亚组，设计AGS特定的临床评定量表，并探索 胰岛素样生长因子与临床疾病的关系。预计这些工具的开发将促进临床 试验性设计，在这种环境下立即使用。