GFAP as an Alexander disease associated biomarker

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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.