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， 星形胶质细胞中的中间丝蛋白、胶质细胞酸性蛋白（GFAP）。令人兴奋的小说 在鼠模型中的研究证明了使用反义寡核苷酸减少异常GFAP的能力 寡核苷酸（阿索）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，领导家庭，倡导团体，临床医生和研究人员寻求迅速启动 的临床试验。然而，将这些发现转化为有效的治疗方法受到缺乏 有数据证明GFAP是未来临床试验的反应性生物标志物。 脑脊液（CSF）和血液是用于GFAP测量的可接近的流体，并且我们的 初步数据表明，AxD受试者的CSF和血浆均升高， 未受影响的对照组。然而，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的功能下降速度较慢，预期寿命较长， 往往跨越几十年。因此，替代终点（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，我们将测量以下患者的CSF和血浆中的纵向GFAP测量值： 多个研究中心的40例亚历山大病患者。我们将测试样品的稳定性， 运输和储存条件以及通过试验内和试验间测量的试验可靠性。 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。这种疾病出现在不同的年龄，具有不同的临床表型，我们将 确定这些特征是否预测GFAP升高。 在具体目标3中，我们将进一步探讨GFAP水平是否预测功能结果 在AxD中测量。我们将利用纵向运动，认知和吞咽工具 项目1在此基础上 这些目标的预期成果是全面了解AxD中的GFAP水平。 这些调查将提供一个关键的知识基础，作为设计的基础 未来的AxD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.