GFAP as an Alexander disease associated biomarker

GFAP 作为亚历山大病相关生物标志物

基本信息

批准号：
10023211
负责人：
Amy Tara Waldman
金额：
$ 17.86万
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/10023211
关键词：
Address Advocacy Age Alexander Disease Antisense Oligonucleotides Astrocytes Ataxia Autonomic Dysfunction Biological Biological Assay Biological Markers Blood Blood specimen Cerebrospinal Fluid Classification Clinical Clinical Data Clinical Trials Clinical Trials Design Clinical Trials Network Clinical/Radiologic Cognitive Collaborations Collection DNA Sequence Alteration Data Data Collection Deglutition Developmental Delay Disorders Disease Disease Progression Enzyme-Linked Immunosorbent Assay Epitope Mapping Family Fiber Foundations Functional disorder Future Gastrostomy Glial Fibrillary Acidic Protein Human Image Individual Intermediate Filament Proteins Intermediate Filaments Investigation Knowledge Laboratories Life Life Expectancy Linear Regressions Liquid substance Macrocephaly Measurement Measures Mediating Medical Genetics Methodology Motor Multi-Institutional Clinical Trial Mutation Natural History Neurodegenerative Disorders Outcome Outcome Assessment Outcome Measure Palatal Myoclonus Pathologic Patients Pattern Pediatric Hospitals Performance Philadelphia Plasma Procedures Production Protocols documentation Qualifying Readiness Reporting Research Personnel Running Sample Size Sampling Savings Seizures Shipping Site Surrogate Endpoint Surrogate Markers Survival Analysis Symptoms System Technology Testing Time Translating base clinical development clinical phenotype clinical subtypes clinically relevant cohort design disease classification disorder subtype early onset effective therapy functional decline functional outcomes gain of function mutation glial cell development illness length individual patient leukodystrophy mouse model novel phenotypic data prospective protein biomarkers protein expression respiratory sample collection tool

项目摘要

ABSTRACT Alexander disease (AxD) is a neurodegenerative disorder caused by the accumulation of an intermediate filament protein, glial fibrillary acidic protein (GFAP) in astrocytes. Exciting novel studies in murine models demonstrate the ability to decrease aberrant GFAP using antisense oligonucleotide (ASO) technology. These advances offer tremendous hope for this devastating disease, leading families, advocacy groups, clinicians and researchers to seek prompt initiation of clinical trials. However, translating these findings into effective treatments is limited by the lack of data qualifying GFAP as a responsive biomarker for a future clinical trial. Cerebrospinal fluid (CSF) and blood are accessible fluids for GFAP measurement, and our preliminary data has demonstrated elevations in both CSF and plasma in AxD subjects over unaffected controls. However, additional studies are needed to first validate the reliability of GFAP testing, and, second, interpret the clinical relevance of GFAP elevations. In contrast to some of the other leukodystrophies, the rate of functional decline is slower in AxD, with a life expectancy that often spans several decades. Therefore, it is plausible that surrogate endpoints (such as CSF GFAP levels) would be considered for early stage trials of short duration. In Specific Aim 1, we will measure longitudinal GFAP measurements in the CSF and plasma of 40 Alexander disease patients across multiple sites. We will test sample stability over various shipping and storing conditions and assay reliability through intra- and inter-assay measurements. In Specific Aim 2, we will determine whether GFAP concentrations vary by clinical subtypes of AxD. The disorder presents at various ages, with different clinical phenotypes, and we will determine whether these features predict GFAP elevations. In Specific Aim 3, we will further explore whether GFAP levels predict functional outcome measures in AxD. We will leverage the longitudinal motor, cognitive, and swallowing tools collected in Project 1 in this aim. The expected outcome of these aims is a comprehensive understanding of GFAP levels in AxD. These investigations will provide a critical foundation of knowledge on which to base the design of future clinical trials in AxD.

抽象的亚历山大病 (AxD) 是一种神经退行性疾病，由星形胶质细胞中的中间丝蛋白、胶质纤维酸性蛋白（GFAP）。精彩小说小鼠模型研究表明，使用反义核酸能够减少异常 GFAP 寡核苷酸（ASO）技术。这些进步为这场毁灭性的灾难带来了巨大的希望疾病，导致家庭、倡导团体、临床医生和研究人员寻求立即启动临床试验。然而，将这些发现转化为有效的治疗方法由于缺乏的数据使 GFAP 成为未来临床试验的响应生物标志物。脑脊液 (CSF) 和血液都是可用于 GFAP 测量的液体，我们的初步数据表明，AxD 受试者的脑脊液和血浆均升高不受影响的控制。然而，还需要进行更多研究来首先验证 GFAP 的可靠性其次，解释 GFAP 升高的临床相关性。与某些相比与其他脑白质营养不良症相比，AxD 的功能下降速度较慢，但预期寿命较短往往跨越数十年。因此，替代终点（例如 CSF GFAP 水平）将被考虑用于短期的早期试验。在具体目标 1 中，我们将测量脑脊液和血浆中的纵向 GFAP 测量结果多个地点的 40 名亚历山大病患者。我们将测试样品在各种情况下的稳定性通过测定内和测定间测量确定运输和储存条件以及测定可靠性。在具体目标 2 中，我们将确定 GFAP 浓度是否因临床亚型而异 AxD。该疾病在不同年龄阶段出现，具有不同的临床表型，我们将确定这些特征是否可以预测 GFAP 升高。在具体目标 3 中，我们将进一步探讨 GFAP 水平是否可以预测功能结果 AxD 中的措施。我们将利用纵向运动、认知和吞咽工具为此目的在项目 1 中收集。这些目标的预期结果是全面了解 AxD 中的 GFAP 水平。这些调查将为设计提供重要的知识基础 AxD 未来的临床试验。