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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $364,206

## Abstract

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.

## Key facts

- **NIH application ID:** 9872214
- **Project number:** 5R01NS105741-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ari J Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,206
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872214

## Citation

> US National Institutes of Health, RePORTER application 9872214, Establishing VEP as a quantitative biomarker for remyelination using transgenic models for gain and loss of function (5R01NS105741-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872214. Licensed CC0.

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