Tuesday, December 7, 2010

Hope, not hype -- stimulating remyelination may be a possible route to multiple sclerosis (MS) therapy

We don't do this very often, but here we point out an excellent use of genetics with a potentially very important therapeutic outcome.  Authors writing in Nature Neuroscience on Dec 5 report that the ability of myelin sheaths in the CNS to regenerate following acute demyelination is limited in dymyelinating diseases such as multiple sclerosis (MS), but that with pharmacological and genetic manipulation methods, they were able to enhance remyelination in rats.  This has the potential to be a significant advance for treating demyelinating diseases. 

The molecular basis of remyelination has not been well-characterized, but it has been known, as stated in the paper, that following demyelination, "adult oligodendrocyte precursor cells (OPCs) can migrate to the area of injury, differentiate into oligodendrocytes and restore myelin sheaths".  In individuals with MS, in part the problem is that following the demyelination episodes that characterize the disease, OPCs don't differentiate into myelinating oligodendrocytes.  (OPCs are the CNS equivalent to Schwann cells, which insulate axons.)

To identify genes of interest in the remyelinating process, Robin Franklin's group demyelinated nerve sheaths in rats with a toxin, and generated a list of all the genes expressed in the lesions during the remyelination process, a complete "transcriptome".  They found thousands of genes differentially expressed over time in the lesions as they regenerated myelin, including, early on, genes involved in the immune response, and later, a number of genes already known to be involved with myelination, cell metabolism and proliferation and differentiation.
These results show that the overall molecular signature of CNS remyelination involves distinct and temporally regulated signaling pathways that are characterized by active inflammation at 5 dpl [days post lesion] and by the initiation of remyelination at 14 dpl.
But one gene was of special interest because it was one of the most significantly upregulated genes at the time when remyelination was occurring, 14 dpl, and clustered with many genes involved in myelination.  This is retinoid X receptor gamma, RXR-gamma, found in the tissue of individuals with multiple sclerosis as well, and involved in the regulation of cell proliferation, differentiation and apoptosis, which they verified experimentally.  The paper shows this to have been a very careful characterization of this gene and its role in remyelination. 

To determine whether they could effectively activate RXR and promote CNS remyelination, they tested the effects of 9-cis-retinoic acid (9cRA) on RXR activity.  9cRA is an RXR ligand which is known to activate transcription of MBP, or myelin basic protein, which is expressed in differentiated oligodendrocytes.  If RXR signaling is involved in differentiation in these cells, it would be via MBP.  It turned out that OPC cultures treated with 9cRA showed indication of OPC differentiation, and in vivo tests of the effects of RXR signaling via this pathway were positive. They then determined that, in culture, in OPCs in which RXR activity was blocked, oligodendrocyte differentiation was inhibited.

So, this series of experiments, from gene discovery to characterization of function, suggests a possible pathway to treatment for demyelination diseases -- stimulate RXR activity.  A short interview with the senior author in the story on the BBC website shows him to be cautiously hopeful, but measured in his promises for a cure. When pressed on when this work might lead to treatment, he said that it was very difficult to say, but perhaps within 15 years. 

The BBC quotes him:
Professor Robin Franklin, director of the MS Society's Centre for Myelin Repair at the University of Cambridge, said: "Therapies that repair damage are the missing link in treating MS.
"In this study we have identified a means by which the brain's own stem cells can be encouraged to undertake this repair, opening up the possibility of a new regenerative medicine for this devastating disease."
The study takes advantage of the idea of genes for processes rather than things per se.  Myelin is, in a sense, an insulating compound: it's not alive, but is secreted by cells. Rather than try to apply some sort of coating to individual nerve cells by therapy the idea is to induce the cells to do it, when they're defective in that process.  That means tinker with signaling!  Thus, the problem here is with a signal reception and the consequent disruption of subsequent signal cascades leadiing to cellular production of myelin. By activating the signal efficiency, the downstream event is triggered -- and no meddling with the many intermediate steps is needed, as they are intact in the individual's genome.  In that sense, or rather in the way we've tried to describe in our book The Mermaid's Tale, it is communication and cooperation that have failed, and here, fortunately, appear to be able to be restored.

This is an excellent example of the use of genetic knowledge to explore a disease and potential treatment pathway.  A lot of work still must be done to figure out, among other things, how to stimulate remyelination in vivo, so caution is warranted.  Still, we hope along with the researchers that their work continues to be fruitful.

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