Establishing VEP as a quantitative biomarker for remyelination using transgenic models for gain and loss of function

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Multiple sclerosis (MS) is an immune mediated disease of the central nervous system in which an aberrant immunological response targets myelin, leading to short-term neurological dysfunction (exacerbations) and ultimately to permanent disability. Demyelination of axons is potentially a major contributor to irreversible neuronal loss and secondary irrecoverable disability. Oligodendrocyte precursor cells (OPCs) are an endogenous pool of oligopotent stem cells capable of replenishing damaged or lost oligodendrocytes and are found throughout the brain and within lesions of MS patients. However, incompletely understood factors appear to inhibit oligodendrocyte differentiation and resultant remyelination after inflammatory injury in MS. The use of EAE as a clinical and immunological model to illuminate MS has contributed significantly to the growing arsenal of immunomodulatory therapies available for treatment. MRI has also been a useful early phase clinical outcome that has helped improve efficiency of selection of compounds for phase III development as immunomodulatory agents. No similar models or methods exist for demonstrating and confirming therapeutic potential for remyelinating agents. In this project we will conclusively establish the histological and ultrastructural correlates of visual evoked potential latency in multiple models of visual pathway demyelination. These systems will allow us to disentangle the role of demyelination from inflammation and axonal loss by using a) genetically engineered models with enhanced and abrogated myelinating capacity, b) a validated remyelinating compound previously assessed by multiple groups in both rodent and human cells as well as rodent spinal cord, c) non-inflammatory demyelinating models using chemical demyelination methods and d) a unique primate monocular chemical demyelinating model. Furthermore, we have completed a phase II clinical trial that clemastine improves latency on visual evoked potentials in human MS patients with chronic optic neuropathy. Our preliminary work suggests that VEP may be more sensitive than clinical scoring for detecting demyelination and/or that the visual pathway itself is sensitive to early injury in EAE. We have optimized a VEP protocol for mice with exceptional reproducibility and high throughput capacity. We have also developed and/or begun working with models capable of dissecting the impact of demyelination, remyelination, inflammation and axonal loss for better understanding the factors that influence VEP signal. This work will help to establish VEP in EAE and confirm the cellular basis of changes on the VEP signal in general. It will thereby resolve a currently unmet need and accelerate the preclinical and early clinical development of therapies for remyelination in MS.