Gene therapy for Duchenne Muscular Dystrophy

One very promising area for gene therapy is in the muscle-wasting disease Duchenne Muscular Dystrophy, which affects about one in every three thousand males. It targets boys because the affected “dystrophin” gene is on the X chromosome, and boys have only one copy of that. If their version of the gene doesn’t work properly, their muscles fail. Previously, there was no way to treat the condition. But now, working at Murdoch University in Western Australia, Sue Fletcher and Steve Wilton have developed a genetic therapy that can “cover up” the damaged part of the gene so the muscle cells can still read the rest of the message and produce a working form of dystrophin. Chris Smith spoke to them...

Sue - Duchenne M.D. is an inherited muscle wasting disease that is usually evident in affected boys around two to five years of age. They walk late, over the age of two, and they have difficulty climbing stairs. They often walk with a little bit of a waddle and they struggle to keep up with their peers.

Chris - And what is actually going wrong in them to make that happen?

Sue - So these boys have a mutation in the dystrophin gene that is located on the X chromosome. Girls have two copies of the X chromosome while boys have only one, and therefore if the single dystrophin gene is non-functional, the essential muscle protein dystrophin is missing. The muscles become very prone to damage and although the kids appear healthy at birth they have these delayed motor milestones and they lose the ability to walk by twelve years of age.

Chris - And what's the ultimate end point for these kids?

Sue - Well all muscles are affected, including the heart, and they usually will succumb to either respiratory failure or cardiac failure in their 20s, sometimes in their 30s, DMD a life limiting disease, it's fatal.

Chris - And Steve, what's the intervention that you and Sue have pioneered here to try to intervene in the process?

Steve - As you mentioned, the problem is a mutation or a spelling error in the genetic instructions for a gene called dystrophin, and the actual gene product acts like a little shock absorber. The ends of it give strength and stability to the muscle fiber. As you can imagine, any spelling error that stops the synthesis of this protein, you end up with a one-ended shock absorber and it can't work. Our approach is to design a drug that acts as a genetic white-out, or a correcting fluid for the gene message. We cover the disease causing part, so we can make a shock absorber that's a bit shorter in the middle. But the ends are intact, then the gene can be translated into a protein that is going to be functional.

Chris - So in essence then, it's almost like a genetic sticking plaster, you can actually put this into cells and when the gene is read, the cells don't see the broken bit of the gene they just see your sticking plaster, which is the correct message, and it skips over or jumps over the broken bit fooling the cell into just reading the whole thing almost, and you get a healthy protein or nearly healthy protein.

Steve - That's right. It's like a genetic Tipp-Ex.

Chris - And Sue, how do you get this treatment into the body?

Sue - The treatment is not the most convenient of treatments. It is delivered by a once weekly intravenous infusion and it's quite a long slow infusion.

Chris - And does that mean then, that when you inject this drug it goes to every cell in the body even though it's only the muscles which are affected, and does that have any consequence?

Sue - You're correct. It goes into the bloodstream so it's distributed throughout the body. But the beauty of this kind of treatment is it can only have an effect where that gene is being expressed. So if the gene is not working in a cell, like in a skin cell or a liver cell, the drug won't do anything. It can only work in muscle where the dystrophin gene message is active.

Chris - And when you do this Steve, what actually is the consequence for the muscle cells that pick up your drug?

Steve - One of the problems is that only a little bit of the drug gets into the cells. The uptake at the moment is a real problem, but the little bit of protein that's being made is making a very substantial difference. Boys, young men now, who should be in a wheelchair, are still walking, respiratory functions have stabilised, and declining much slower than they would in untreated boys. So it is working, but we have to make it work a little more efficiently, and that's why we’re improving delivery or increasing the potency of the drug. And these studies are ongoing.

Chris - And Sue, how many patients have you treated so far?

Sue - The trials and the drug now is on sale in the USA. I don't have a number of patients who have been treated overall, but the original trial involved twelve boys aged between 9 and 11, and that's kind of the time when most of them would be expected to be slow, their walking ability would be declining pretty rapidly, and they'd be mostly expected to be off their feet by 12 years of age. We never expected that the drug would reverse the disease. We did hope it would slow the decline or partially stabilise it. And Billy who is the star of trial, or one of the stars of the trial, he's over 18 years, so he's been treated for over nine years now and he walked to the stage at his graduation. This is unprecedented in a boy with Duchenne.

Chris - Indeed because I've actually met Billy, because you brought him to Western Australia to a conference you were presenting at. And this is a few years ago now. He actually ran into the room

Sue - Yes, that's Billy

Steve - With his type of mutation, He should have stopped walking at eleven point one years of age. According to statistics.

Chris - So how does that make the pair of you feel then, I mean you must be delighted?

Steve - Chuffed, and also overwhelmed because we want to make this work for so many other kids. The treatment is designed for one type of mutation. We've got treatments for many, many different types of spelling errors in the gene. And we really want to see that out there.

Sue - As a researcher, it's an extraordinary position to be in, to actually see somebody whose life has been changed by the work that our group have done.

Chris - And any side effects of using this therapy?

Sue - All drugs have side effects, so the pain at the injection is a side effect of the treatment. But to date, there have been no drug related serious side effects which is really quite as extraordinary, it’s largely to do with the chemistry. It's neutral, so it doesn't stick to things very well, which is why it's not efficiently taken up by cells. But to date, there is no evidence that this drug causes any adverse effects on the cells. These boys are being treated for nine years with no side effects.

Steve - The most serious side effect I've heard of so far is a broken ankle, he was running!