Plasma neurofilament light chain as a potential disease monitoring biomarker in Wolfram syndrome

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Wolfram syndrome (OMIM #222300) is a rare autosomal recessive disorder, characterized most frequently by childhood-onset insulin dependent diabetes, optic nerve atrophy, sensorineural hearing loss, and diabetes insipidus. Symptoms appear in early childhood and increase over time, ultimately resulting in blindness, deafness, ataxia and other significant neurologic symptoms by early adulthood. Longitudinal analyses have demonstrated that specific clinical (e.g. visual acuity, color vision) and derived neuroimaging variables (e.g. thalamic & ventral pons volumes) deteriorate over time. These measures are now being used in an ongoing clinical efficacy trial (ClinicalTrials.gov Identifier: NCT03717909). However, they are also costly, time- consuming and require specialized on-site equipment and expertise. In contrast, a biofluid-based measure of neurodegeneration would be cheaper, more easily standardized and repeatable, and thus extremely useful for ongoing and future clinical trials designed to slow or halt neurologic progression. Emerging biofluid markers of neurodegeneration, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), appear sensitive but non-specific in neurodegenerative diseases. NfL levels are greater in plasma of individuals with Wolfram syndrome compared to controls while GFAP has not been studied in this disease. We need to understand if NfL is elevated in Wolfram independent of potential confounders including diabetic status and age, whether its levels change over time and whether these changes track the progression of neurologic symptoms. Clinical validation of NfL, and possibly GFAP, measured in the same blood sample using the same assay, is an important precursor to proposing the use of NfL and/or GFAP in intervention studies or conducting neuropathological validation studies in animal models. This proposal is focused on these necessary next steps and, if successful, will provide a strong platform for using NfL and/or GFAP to monitor neurodegeneration in Wolfram syndrome.