Trying to help find the cure for MS using genetics

A/Prof David Booth presents how his lab is trying to help find the cure for MS using genetics.

Transcript of Presentation
 

Hello everyone, I’m David Booth. My lab is trying to help find the cure for MS using genetics. We know that MS is a disease that has a genetic and an environmental component and that if you can identify the genes which are involved that will surely help in finding a cure. So there is some very good news on that front. Some milestone achievements as a result of giant collaborations and new technologies.

In 2007 we knew just one gene which was effecting MS, now as a result of this collaboration, which is groups from Cambridge from all over the UK, from Europe, from the USA, from Australia, from New Zealand they all got together and did this massive experiment which involved DNA from 10,000 people with MS and DNA from 10,000 healthy controls and to find the genetic variants which were different.

This experiment had enough, at last, power to answer the question and so the results are going to be released in about a month. I can tell you now that we have gone from one to fifty-seven genes which effect MS. As a result of this experiment.
I should say this experiment was very, very expensive. It was funded largely by the Welcome Trust, but then every group who contributed to it also needed funding. In our case we were funded by MSRA and NHMRC and it was a big collaboration the ANZgene collaboration which contributed Australia’s component to this.

We were very lucky with the first gene, just knowing the genes, we know have fifty-seven genes what are they going to tell us. Potentially there are gold nuggets there, but you have to work out why they’re associated with MS, why they’re effecting MS and it is not always going to be easy. The first gene it was easy. That was called HLADRB1.

Because that gene has a great trade it is only expressed on one type of cell and only does one thing. Which is activates CD4 T-cells. So from knowing the gene was associated with the MS. You knew straightaway CD4 T-cells effect MS. So you could target CD4 T-cells as a rational approach to coming up with a therapy.

In fact, see that little peptide there, that is captured by the gene and presented T-cells. That is actually the basis for one of the drugs Glatiramer acetate which is designed to be that very peptide.

Then the fact that it shows the importance of CD4 T-cells in immunopathogenesis also supported all the clinical trials that needed to be done on finding other ways to modulate T-cells. That is the Natalizumab and the Tysabri. Tysabri stop CD4 T-cells crossing the blood brain barrier. It all fits into a common picture. But then looking at the 56 other genes. We don’t get No. I hope that doesn’t look too complicated. This is the dominant paradigm as of 2005 and it hasn’t changed.

The idea is that these cells which express that gene DRB1 activate the T-cells, the T-cells cross the blood brain barrier and they orchestrate an auto-immune attack on the myelin sheath of the neurons. That’s a dominant paradigm. Then what did the genes tell us? Well the genes tell us that as it happens all of those genes where we know where they are produced and what their functions are, they are all immune 100%.

So it is looking like this is the part, which the genetic susceptibility is about. Doesn’t mean that pathogenesis doesn’t involve other neuronal components, because obviously it does, but the genetic variation is due to the immune response.
Specifically what does it tell us about the immune response that we can then use to devise new therapies. Answer at the moment it actually tells us quite a few things, because we know those genes are largely about T-cell differentiation, particular types of T-cells.

Here are the usual suspects. There are a number of T-cell subsets and as a result of knowing these genes we will be able to work out which of these T-cell subsets are most important in MS, because they are the ones which will express the genes associated with MS and where the genes will have their effect.

And so research now will be targeting particularly that one and that one. Because there is all sorts of other evidence that they are prime culprits in the MS pathogenesis. But we have to do the work now to find out why these fifty-seven genes affect these T-cells.

It is not all about genetics susceptibility, you can use genes in other ways. This is my last slide. What we see there, this is the idea of using markers. Genetic markers or gene expression markers can hopefully tell us who might respond to what drug and are they responding to the drugs. So it could be clinically useful.

This was an experiment we did as part of the ANZgene collaboration which is funded by MSRA and ARC Linkage project. What you are seeing there is every column is an individual. You have a bunch of controls and a bunch of people with MS and every row is a gene so there is about 200 genes that you see there.

When you see red that means it over expressed and when you see green that means it is under expressed. You can see there is a signature for MS. These genes are all over expressed and these genes are under expressed. These genes are mainly activating T-cells. So this fits with the genetic information.

We are hoping we are going to be able to use this, we expect this redness to turn to green upon therapy for example. We have to do that experiment to so if that truly is the case.

You can also see that some people with MS are green and some people are red and some people that are controls are red there and some are green. So some people have the signature anyway which is presumably susceptibility to auto-immune diseases. Which these people have, but they haven’t got a disease.

A lot of work to do there to make that useful clinically. So I will just wrap up by saying we have got 57 genes we have got to find out why they are causing MS and we have got other things to do with genes to find out how to use them clinically. Ok.