Muscular Dystrophy Treatment

A breakthrough for the disease muscular dystrophy now, thanks to two Murdoch University researchers Steve Wilton and Sue Fletcher...

Sue - Duchenne Muscular Dystrophy is a life-limiting neuromuscular disease that results in losing the ability to walk by the age of 12 and they don't usually survive beyond their early 30's. The gene responsible for the disease is on the X chromosome, so it mainly affects boys but about 1 in 50,000 girls has the disease. Mutations in this gene prevent the synthesis of a protein called dystrophin which is a very important structural protein in muscle and that's in all muscles - heart, skeletal muscle, and in the smooth muscle of the gut.

Chris - So, when an individual has muscular dystrophy, what goes wrong in their muscles? What would a person notice about them?

Sue - Boys with muscular dystrophy do not reach the same motor milestones as other children. Typically, the boys are not walking until perhaps the age of 2. They don't climb stairs very well. They have to hold on to someone to climb stairs. They don't jump with both feet up off the ground and they don't run as other children do, they struggle to rise from the floor and that's very characteristic in this disease.

Chris - And if I were to take a little piece of muscle away and look at it under a microscope, how would it differ to a person who doesn't have muscular dystrophy?

Sue - Somebody with normal muscle, if you take a piece of muscle and you cut across the muscle, it looks like a bundle of straws. The muscle fibres are nice, regular, they're much the same size. When somebody has muscular dystrophy, the muscle is disorganised. It's full of fat and connective tissue and lots of little inflammatory cells chewing up damaged muscle. In advanced disease, it doesn't look like muscle at all.

Chris - Do we know why, not having that dystrophin protein working properly in the muscle makes that happen?

Sue - Dystrophin provides strength and stability to the muscle during muscle contraction. So, when the protein is missing, the muscle gets little tears when it's under strain, when it contracts. And gradually, inflammatory cells start to chew up the muscle because it looks like damaged tissue and the body cleans it up. So, the muscle is gradually replaced with fat and scar tissue.

Chris - Steve, what can we do about this?

Steve - One of the ways we've been trying to treat this disease is changing the expression of the defective dystrophin gene. The dystrophin gene is the largest known gene. It makes up almost 0.1% of our genetic makeup. 2.3 million letters in this one gene. It's been estimated that the enzyme that starts making the RNA copy takes 16 hours to get from one end to the other. It's like a book with 79 chapters. The first few chapters code for the attachment point at one end. The last few chapters are important at the other end. So, what happens in Duchenne Muscular Dystrophy, there's a spelling error somewhere in the chapters. And so, there's a part of chapter 16 that says, "Stop reading at this point." So, the shock absorber is made up to chapter 16 and then the rest of the message is lost. So, we have a defective shock absorber. It's not going to work. You're getting weak muscle fibres.

Chris - So, can we persuade muscle cells when they're reading this book to skip over the chapter that's got this instruction so that it would carry on through to the end?

Steve - That's is exactly what we're doing. We've designed genetic band aids that can stick at or near the defective chapter. And so that, imagine a book with the 79 chapters, it's sticking all the pages together of one chapter. So, it's chapter 15 is joined to chapter 17 rather than having chapter 16 which is the disease causing part.

Chris - Can you just explain exactly what these genetic band aids are? How do they work?

Steve - They're called anti-sense oligonucleotides. They're short genetic fragments that will stick to the dystrophin message. Now, the dystrophin message is called the sense strand and the fact that these are complimentary to the sense strand makes them anti-sense.

Chris - So, they're effectively the genetic mirror image of the gene that is in the cells that's gone wrong. So, how do they make the cell stick the chapters together?

Steve - What happens is that the cell machinery recognises parts of the gene message that have to stitch one chapter to the next. So, we're interfering with the recognition of a chapter. It essentially sort of tapes all those pages of defective chapter together.

Chris - So, when your genetic band aid is stuck on, it effectively crow bars the cell's machinery and says, "Ignore this bit and go on with the next bit."

Steve - I actually use the analogy of a spanner. We're dropping a spanner into this splicing machinery so it clogs up that part of the process and it skips over it completely.

Chris - Have you got to the stage where you've got evidence this is actually working?

Sue - Well, we've had closer than 20 years of animal experimentation and cell experimentation, showing that we can do this in a dish with cells and we can do it in mice. But a mouse is a very small animal. The longest muscle in a mouse is about a centimetre long. So, we have a lot of evidence showing that if we treat young mice, we can abrogate the onset of the disease. We can stop the disease process beginning in these mice by making the muscles and that's all the muscles, make dystrophin. So these mice, their muscle looks like normal muscle.

Chris - So, how do you get Steve's genetic band aids into the mice?

Sue - We inject them into the mice. It's very simple. We dissolve the compounds in saline, salty water, and inject them into the mice. And we've been working with a company that has taken this to human trials and they do exactly the same thing. They dissolve the anti-sense oligos in saline and they inject it intravenously over about an hour, and there are 12 boys have been treated. In the current clinical trials, there have been some previous trials. They have now been treated for over 80 weeks and they have stabilised. So, they measured the distance the boys can walk in 6 minutes and over 80 weeks, those who have been treated are essentially walking the same distance 80 weeks later. And the natural history of the disease tells us that these boys, many of them would've been expected to stop walking by now. And one of the clinicians working on the trials says that in the history of this disease, this is unprecedented.

Chris - And this requires regular therapy. They would come and see someone in the clinic say, what, every week for a top up of the genetic band aid.

Sue - At present, the boys are being treated every week. We don't know if this is the optimum treatment, but this is what clinical trials are for, to first of all prove that the drug is safe. Secondly, to prove that the drug does what it's supposed to do. In other words, preserve the muscle, restore muscle function, and ultimately, there will be additional trials to determine how often and how much of the treatment is required to keep the boys well.