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Muscular dystrophy - genomics raises hopes -

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Duchenne Muscular Dystrophy is a degenerative disease that strikes around 1 in 3,000 boys every
year. Symptoms appear when they are toddlers and most do not live beyond their early twenties.
There is currently no effective treatment, but now some new work is giving hope. Professor Dame Kay
Davies from the University of Oxford explains how they can trick muscle cells into thinking they
are in the developmental stage so they produce utrophin, a protein that can completely remove all
muscular dystrophy symptoms. Following successful animal trials, human trials have started and she
is very optimistic about the future.


Robyn Williams: Our first scientific superstar today is a mere dame, Dame Professor Kay Davies is
director of the Functional Genomics Unit at Oxford where they drill down on genes causing killer
diseases like muscular dystrophy, affecting millions of boys, find out what's missing and try to
fix it. And the news now is brilliant.

Kay Davies: Yes, the disease we're looking at in particular, Duchenne muscular dystrophy, there's
only one very large gene involved. In fact, it's bigger than ten other genes at least, so it's the
biggest gene in the human genome, the biggest gene you'll find in a cell, and it's missing in
Duchenne muscular dystrophy patients.

Robyn Williams: How many bits has it got to make it so big?

Kay Davies: It's got 79 little bits spread over an awful lot of distance along the DNA strand.

Robyn Williams: How does a lump like that get missed out?

Kay Davies: Well, we don't know the mechanism as to why it gets missed up, but 60% of patients have
bits of that gene missing, so it's a highly mutable, fragile part of the cell. It happens quite

Robyn Williams: So if 60% have it missing, presumably it's on the other strand making up for the
missing part, is that right?

Kay Davies: Yes, it is. So in females when you've got two X chromosomes, because it's on the sex
chromosome, then you'll get compensation. So females are carriers and don't usually manifest the
disease unless there's something wrong with the other chromosome. Whereas males, who only have one
X chromosome and a Y chromosome which makes them male, don't have any compensatory effects,
therefore have the disease.

Robyn Williams: And that manifests as they're growing up, their muscles fail. How do they fail in

Kay Davies: They have difficulty walking. The first signs are that they can't get up from the floor
very easily, so they push themselves up on their knees. And then they have difficulty running,
particularly climbing up stairs.

Robyn Williams: Can anything be done for them?

Kay Davies: There's no treatment that's really effective, and that's the tragedy of the disease
because when we discovered the gene a long, long time ago, several people in the world, we
developed a prenatal diagnosis and we could get rid of all familial cases in those families that
wanted prenatal diagnosis, but it's got such a high mutation rate in all populations in the world,
so of all the diseases that need a treatment, this is one, because unless we can screen every
pregnancy we're never going to get rid of it.

Robyn Williams: How do you treat it perhaps using a genetic approach?

Kay Davies: You can either replace the gene, but it's rather big, so you can make mini genes that
do half the work, or you can stick the good bits that are left in the cell back together again to
make a smaller protein which might function partially, and that does work to a certain extent. Or
we discovered a protein that's very closely related to the missing one which isn't on the X
chromosome, and we've showed in animal models that if you increase the levels of this protein,
which is called utrophin, the missing one is called dystrophin because it causes dystrophy, then
you can compensate completely. So you can cure the mouse by increasing the levels of this protein.

Robyn Williams: How do you get the protein in?

Kay Davies: You can either deliver it by injection or you can use a drug just like any
pharmaceutical drug which will act on the machinery in the cell which will override what's causing
the utrophin to stay at low levels in muscle and make it produce high levels. The reason we were
hopeful that that would work is if you look at early human foetal development, this other protein,
utrophin, is present before dystrophin, and then dystrophin comes up and they're both there
together in the muscle, and then the cell gets rid of utrophin and puts dystrophin in its place. So
some time in human development utrophin is replacing dystrophin. So what we are trying to do is get
a drug that will make the cell think it can recapitulate early human development. And if we can do
that then we'll have an effective treatment for the disease.

Robyn Williams: I would have said yourself you found this gene a long time ago, and
you've got the model in mice, surely if something looks as if it might work in a situation which is
so dire for the poor young boys, isn't there a case for going in there anyway and hoping?

Kay Davies: Well, you don't want to kill the patient, for a start. So it's taken us two or three
years to do all the drug screening, and then we identified one compound which did do that in mice,
and so we're now able to take that compound forward into human trials. So we've partnered with
BioMarin Pharmaceuticals in the States, and they will now take that compound through...the first
thing is to test it in normal individuals to make sure it isn't harmful and then, you're quite
right, hopefully the FDA will give us permission to go into young boys, because the younger we go
in, the more chance we have of the job being effective before they've lost their muscles

Robyn Williams: How long do they usually last, what age?

Kay Davies: That's got better with better management and respiratory support. We used to say late
teens but a lot of them live into their early 20s now.

Robyn Williams: This is a success story in muscular dystrophy, but you're looking right across the
board at a number of what?

Kay Davies: There are other examples where you can use related proteins, and actually we
collaborated with a group in Western Australia, Nigel Lang and Kristen Nowak, to look at a disease
where actin is missing. You have actin in your skeletal muscle which is different from that that's
in your cardiac muscle. What we demonstrated is, again, same principle, if you could increase the
levels of cardiac muscle artificially in the skeletal muscle, you could cure the mouse that had the
disease. But I'm also interested in neurodegenerative diseases like motor neurone disease, finding
those genes which put people at risk of having motor neurone disease, Parkinson's disease, ataxia
which is trembling hands. A lot of these are common pathways, and so what we're trying to do is
identify the common pathways so we can target those for drugs and maybe come out with a clinical

Robyn Williams: Yes, I broadcast that example from Western Australia two or three months ago, and
it's quite fascinating when the muscles have got two ways of operating, they're either general body
muscles or heart muscles, and in some way if you can fool the body into using the heart muscle
design instead it kind of works. And instead of being floppy and the baby is unable to move,
suddenly they're able to be almost normal.

Kay Davies: Right, so that's what we would hope with a drug treatment, early on again, that we
would be able to affect that treatment in young babies.

Robyn Williams: This seems to be a wonderful way of getting into the genes themselves. It's an
exciting time, isn't it.

Kay Davies: You're telling me, absolutely. I mean, it changes every minute actually, and to think
that when we first discovered utrophin it took us two years to clone it, that means to get it in a
test-tube so we could study it, and if I had it now it would take me less than week, and people are
sequencing whole genomes in less than a week. So that gives us enormous power to be able to take some spinal cord from a diseased patient who's got ALS, say, motor neurone disease,
and we can punch it out in one bit, that's diseased, and we can look at all of the genes that are
expressed, including these RNA molecules I'm talking about, and you can take the bit next door
which is normal, you compare the normal bit with the diseased bit and you begin to understand the
gradation, what's the difference between that bit of diseased spinal cord and that bit of normal
spinal cord in the same patient. You could never have done that even a year ago.

Robyn Williams: A final question, there are plenty of families listening whose boys have got
muscular dystrophy, what really can we tell them about the prospects in the next one or two or
three years?

Kay Davies: I think you will definitely see successful clinical trials that will be able to go out
there and be applied to more patients in the future. I'm very optimistic, and I've never said
that...well, I've started to say that since a year ago; I am optimistic.

Robyn Williams: That's Dame Kay Davies at the physiology department at Oxford, one of the legends
in her field. If she's optimistic, we can be as well.


Kay Davies

MRC Functional Genomics Unit University of Oxford


Robyn Williams


David Fisher