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Validating visual evoked potentials as a preclinical, quantitative biomarker for remyelination efficacy

Cordano, C;Sin, JH;Timmons, G;Yiu, HH;Stebbins, K;Guglielmetti, C;Cruz-Herranz, A;Xin, W;Lorrain, D;Chan, JR;Green, AJ;

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease – and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the central nervous system are lacking. Therapies with potential to remyelinate the central nervous system constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential (VEP) have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on VEP, the interpretation of these trials is constrained. The VEP was originally developed and utilized in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to VEP latency in both inflammatory and chemical models of demyelination. VEP latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve VEP latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that VEP measures myelin status and is thereby a validated tool for preclinical verification of remyelination.