Myelin Repair

Myelin Repair
 

Research Presentation from Dr Ben Emery.

Transcript of Interview - Myelin Repair

RESEARCH PRESENTATION - MYELIN REPAIR

BEN EMERY
My name is Ben Emry. I’m a senior research fellow at the University of Melbourne and the Howard Florey Institute. I’m working in Trevor Kilpatrick’s MS group
I’m primarily interested in understanding the events that drive the myelination process. This is both during normal development. Usually in humans, myelination occurs in the first 18 years of life.

But also in understanding how that relates to myelin repair in human diseases such as MS. So I’m interested in the factors that either promote or inhibit the formation of myelin by oligodendrocytes.

The research project I’m engaged in is trying to understand the role of a transcription factor. A transcription factor is a gene that controls the expression factor of a wide number of other genes. I’ve identified a transcription factor that is vital to the development of the mouse for the generation of myelin. And I’m now taking this transcription factor and trying to understand its role in remyelination or myelin repair in mouse models of MS.

Essentially this transcription factor is only expressed by mature oligodendrocytes within the brain. This transcription factor, which we call the myelin-gene regulatory factor, or MRF, is only expressed within the brain by the mature myelination oligodendrocytes. This is what gave us our first lead, but it might be important in having a role in myelination because it was only expressed by the myelinating cells.

I use a number of different models to investigate the role of this transcription factor. Primarily I use genetically modified mice in which this transcription factor is either over expressed in our cell type of interest, oligodendrocytes, or the gene encoding this transcription factor is actually deleted in oligodendrocytes. So they are unable to express it normally.

I also use quite a few tissue culture models where we can take these oligodendrocytes out of the mice or rat and culture them over a long period in tissue culture dishes. And also, manipulate the expression of a gene in that context. We also use biochemical models and mouse models of MS where we can induce demyelination and then look effectively in myelin repair in these mice.

So the ultimate goal is basically to identify strategies where we can promote remyelination in the context of MS. It’s really been shown over the years, initially or in the early stages of MS, remyelination occurs relatively efficiently but as the disease progresses this remyelination process seems to become less and less efficient.
This is probably quite a large contributing factor to the progression of the disease.

So what we’re hoping is that if we can identify ways of promoting the efficiency of remyelination and combine this with the current modulatory treatments, we can get a dual approach that improves the outcome of MS.

If we can prove that in a mouse model that modulating the expression of its transcription factor can improve the efficiency of remyelination, then next steps are to find ways we can modulate its expression in human or at least animal models without using genetic manipulation. Relevant to this is several pharmaceutical companies would have expressed interest in setting up screens for instance, its components over the effect of expression or activity in, for instance, cultured cells. Using this as a screen you can start looking for drugs that you can then put back into the animal models. Or you can screen ones to improve the efficiency of myelination. The hope would be that if we can find agents that promote the expression of this transcription factor and also the efficiency of remyelination in mice, then they would serve as the basis for human drug trials down the track. At the moment we don’t have any agents that we know of that with promote or inhibit the expression of this transcription factor.

Unfortunately I think this sort of research is always very slow. From the point that we identify a target of interest, in this case a transcription factor, you then have to identify strategies to modulate its expression. That’s going to take several years. There’s then going to be corresponding dosage experiments in mouse models for instance. That’s probably going to be several more years. And then you’re looking at another several phases of clinical trial, which is like a five year endeavour.
So the point of discovery in laboratory to the point of getting a human therapeutic on the market, you’re probably talking about anywhere in between 10-20 years.

One of the other areas that I’m really interested in is understanding what signals the neurons or nerve cells provide to the oligodendrocytes, to promote or inhibit the myelination. So it’s known that neurons are instrumental in dictating whether or not the connections they form with other neurons are myelinated.
And understanding, essentially they can express signals on their cell surface that either says, myelinate me or don’t myelinate me. and it’s quite possible that changes in these signals during the course of MS may dictate why some MS lesions go on not to myelinate.

One of the questions I’m particularly interested in is, what are the signals that neurons can produce that determine whether an oligodendrocyte can myelinate or not? At the moment I’m currently running a screen for a series of candidate genes expressed by neurons and receptors for these factors on the oligodendrocytes to see which have effects on myelination both in animal models and also tissue culture models of myelination.

At the core of this project itself, but I’m working in a much larger umbrella group that’s headed by Trevor Kilpatrick who has a large group looking at various different aspects of MS research including genetics.

Working more closely with me I have one research assistant and also a very talented post-doc who has recently joined me. And hopefully over the next several years I’ll have students joining my group and also working on these projects.