GFAP as an Alexander disease associated biomarker

摘要 亚历山大病(AxD)是一种神经退行性疾病，由积聚的 星形胶质细胞中的中间丝蛋白、胶质纤维酸性蛋白(GFAP)。激动人心的小说 在小鼠模型上的研究表明，使用反义基因能够减少异常的GFAP 寡核苷酸(ASO)技术。这些进展为这场毁灭性的 疾病、领导家庭、倡导团体、临床医生和研究人员寻求迅速启动 临床试验的结果。然而，将这些发现转化为有效的治疗方法受到缺乏的限制 数据表明GFAP有资格作为未来临床试验的响应性生物标志物。 脑脊液(CSF)和血液是GFAP测量的可获得的液体，我们的 初步数据显示，AxD受试者的脑脊液和血浆均高于 未受影响的对照。然而，还需要更多的研究来首先验证GFAP的可靠性 第二，解释GFAP升高的临床相关性。与一些 在其他脑白质营养不良中，AxD的功能衰退速度较慢，预期寿命较长 这往往跨越了几十年。因此，代理端点(如CSF)似乎是可行的 (GFAP水平)将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纵向GFAP的测量 40名亚历山大病患者，分布在多个地点。我们将测试样品在不同环境下的稳定性 运输和储存条件以及通过试剂盒内和试剂盒间测量的分析可靠性。 在特定目标2中，我们将确定GFAP浓度是否因临床亚型不同而不同。 AxD。这种疾病出现在不同的年龄，具有不同的临床表型，我们将 确定这些功能是否可以预测GFAP高程。 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 轴D中的测量。我们将利用纵向马达、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的GFAP水平。 这些调查将为设计提供重要的知识基础 未来在AxD进行的临床试验。

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.