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New Clues to Remyelination Provide Potential Targets for MS Therapy

ARTICLE IN BRIEF

Dr. ROBIN J. M. FRANKLIN said the investigators are now testing compounds that regulate

RXRpathways to see whether they can enhance natural remyelination processes.

In animal models and tissue from MS patients, investigators observed that retinoid X receptors regulate oligodendrocyte differentiation and could be a potential target for therapies.

A team of British investigators have tapped into the molecular pathway involved in CNS myelin regeneration and found that a specific gene that encodes a retinoid acid receptor was differentially expressed during remyelination. Specifically, RXR-gamma was turned up in cells of the oligodendrocyte lineage in animal tissue undergoing remyelination and in active and remyelinated multiple sclerosis (MS) lesions.

The findings, published in the January Nature Neuroscience, suggest a potential target for a new generation of therapeutic agents that help regenerate damaged cells in MS.

Lead author Robin J.M. Franklin, PhD, professor of neuroscience at the MRC Centre for Stem Cell Biology and Regenerative Medicine at the University of Cambridge, said the experimental work supports the role of retinoid X receptors (RXRs) — nuclear receptors that regulate cell proliferation and differentiation — in regulating oligodendrocyte differentiation.

RXR-gamma emerged from a comprehensive transcriptional profile of an experimental model of demyelination and remyelination.

“This remyelination transcriptome will be a useful resource that should allow the neuroscience and the regenerative medicine community to better understand the signaling networks and factors that are required when endogenous precursor cells repair the injured brain, as well as how normally expressed genes and signaling pathways in the white matter might be affected in pathologies of CNS demyelination or failed myelin regeneration,” the study authors wrote in the paper.

STUDY PROTOCOLS

The investigators used a toxin to induce demyelination in a rat model and then used microdissection and microarray analysis of the lesion to identify the genes turned on or turned off during different stages (five, 14, and 28 days after injury) of spontaneous CNS remyelination. They did similar studies on CNS tissue from MS patients with active and inactive lesions.

In the animal models of acute focal demyelination, RXR-gamma stood out as a clear player among all of the genes identified. While RXR-gamma was barely expressed at day five post-lesion, it showed an eight-fold increase at day 14 and continued to be highly expressed at day 28.

Dr. Franklin said that supports the “idea that it is actively expressed at the onset of remyelination.” (The genes highly expressed at day five are associated with inflammation, he said.)

They also looked at postmortem tissue from patients with MS, including two with secondary progressive and one with relapsing-remitting MS. They had a non-neurological sample base of three controls. Active lesions had a significantly greater density of RXRs than controls (p<0.001) and chronic, inactive lesions contained fewer RXR cells (p<0.05) than normal white matter.

Once they understand the molecular signals, the investigators hope to target the genes that regulate the proliferation and differentiation of adult oligodendrocyte precursor cells. Dr. Franklin said that there are already drugs used to treat other diseases that work on some of these molecular targets. For instance, the cancer drug bexarotene hits the RXR pathway.

EXPERTS COMMENT

Commenting on the study, Bruce Trapp, PhD, chairman of the neuroscience department at the Cleveland Clinic Lerner Research Institute, where he runs a rapid autopsy program for MS, said he believes this kind of work may ultimately hold hope for MS patients.

“The adult brain needs new oligodendrocytes to make myelin,” he said. “If you take oligodendrocytes and inject them into the brain they will not make myelin. But if you take oligodendrocyte precursor cells and put them into brains they generate new oligodendrocytes that make myelin. And it is this remyelination that will be neuroprotective and save the axons.”

“We now believe that modifying or enhancing the body's own repair mechanisms is an appropriate way to attack MS,” said Dr. Trapp, who founded a company called Renovo Neural, Inc. that is developing small molecules that work on these brain repair mechanisms.

Steven Goldman, MD, PhD, chairman of the neurology department and the Edward A. and Alma Vollertsen Rykenboer Chair in Neurophysiology at the University of Rochester, works with and sees the potential of oligodendrocyte precursor cells, but he contends the work is a long way out from any human disease application. “Enhancing this population of cells has never been tried in animal models of disease,” he said. “We have a lot more to learn before we go to the clinic with these approaches.”

Dr. Goldman, who was not involved with the study, said he worries that such induction strategies could be risky. “I'm a big fan of potential induction or mobilization strategies, but with eyes wide open. Despite their great long-term promise, these approaches have challenges and potential risks that must be anticipated and managed. So for example, tumorigenesis typically requires or follows genetic mutation, so that exogenous activation of progenitor cell signaling pathways alone is generally not sufficient to induce gliomagenesis. Nonetheless, induction or mobilization of endogenous progenitors needs to be entertained cautiously because of the risk of initiating gliomas or other brain cancers from mutated tumor progenitor cells that may have been otherwise latent or quiescent.”

DR. STEVEN A. GOLDMAN said he sees the potential of working with oligodendrocyte precursor cells, but he contends the work is a long way out from any human disease application. “Enhancing this population of cells has never been tried in animal models of disease,” he said. “We have a lot more to learn before we go to the clinic with these approaches.”

Dr. Goldman is more excited about the possibilities for transplanting these cells to treat genetic conditions where myelin is absent or damaged. In these diseases, such as the leukodystrophies, all of the cells have the same deficiencies, and transplanting healthy populations of these cells could myelinate the brain.

REFERENCE:

Huang JK, Jarjour AA, Franklin RJM, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 2011; 1(14): 45–53.