Jeff Chamberlain first heard about muscular dystrophy as a kid watching the annual Jerry Lewis telethon on Labor Day weekend. That TV program has been raising awareness for 43 years about this genetic disorder that breaks down muscles, eventually crippling and killing young boys and men, usually by their 20s.
The disease really captured Chamberlain’s curiosity about 25 years ago, when in graduate school he started studying the basics of how muscles form. He’s now a professor of neurology at the University of Washington, and a leading researcher attempting to develop the first drugs that can go beyond treating the symptoms of muscular dystrophy, and actually affect the underlying genetic disorder. He’s also a scientific advisor to CureDuchenne, an advocacy group for patients with the most common form of the disease, Duchenne Muscular Dystrophy.
Biotech companies haven’t shown much interest in muscular dystrophy, although that’s changing as researchers gather understanding of the genetic underpinnings of the disease. One leading candidate in this new class of treatment is from Bothell, WA-based AVI Biopharma (NASDAQ: AVII). The AVI treatment is part of an emerging class of compounds known as antisense oligonucleotides. It’s designed to silence a specific stretch of RNA that can enable the body to produce a protein called dystrophin. The protein is essential for muscles to be able to rebuild themselves, and is lacking in patients with muscular dystrophy. The drug recently earned notice in The Lancet when it showed an ability to restore some production of dystrophin proteins in an early-stage clinical trial—although it didn’t fully restore the dystrophin.
If AVI can show in subsequent trials that its drug is safe, and can be delivered throughout the body, it would be a big step forward even if it’s modestly effective, Chamberlain says. About one in every 3,500 boys born worldwide have Duchenne Muscular Dystrophy.
Chamberlain spoke with me in depth about how the standard of care for Duchenne Muscular Dystrophy has evolved, which drugs show promise in development, which companies are leading the way, and what patients can realistically expect from treatments of the future. Here is an edited account of the interview:
Xconomy: How did you first get interested in Duchenne Muscular Dystrophy?
Jeff Chamberlain: In graduate school, I was more interested in developmental biology, in terms of how does a human body form from a single fertilized egg. I ended up in a laboratory that was studying muscle development, as in how does muscle form. I wasn’t focused on diseases, but became interested in muscle tissue, and as soon as you start working on muscle, you hear about the muscular dystrophies because it’s a common genetic disorder.
I grew up watching the Jerry Lewis telethon, every Labor Day, which the Muscular Dystrophy Association puts on. A lot of the funding for basic muscle research was coming through the Muscular Dystrophy Association. So you couldn’t help but want to learn more.
The focus of my project was the importance of genes in regulating muscle growth. So when I graduated and went off to do postdoctoral training, I was recruited by a lab that wanted to study the genes involved in muscular dystrophy.
X: What year was this?
JC: About 1985. This was before any of the genes were known that cause muscular dystrophy.
X: Was the thinking then that this was a single gene disorder?
JC: Yes, that was known even then. Because all the muscular dystrophies are inherited diseases. Just from the pattern of transmission within families, it was known they were single gene disorders. There are a lot of different kinds of muscular dystrophy, but the majority of cases are Duchenne Muscular Dystrophy. This is a disease that has received a lot of focus, because it is the most common inherited disease in the world in terms of single gene disorders. It’s more common than cystic fibrosis. More common than hemophilia.
We know now that it’s the largest gene in nature. It’s almost 2.5 million base pairs in size. An enormous gene, almost 10 times bigger than any other gene, so there are a lot of things that can go wrong with this gene. A lot of things can get messed up pretty easily.
X: Given how common it is, and how much attention has been placed on this disease over the years because of Jerry Lewis, why hasn’t there been more progress?
JC: There’s been a tremendous amount of progress, but it’s been a very difficult situation. At the moment, we really don’t have a cure for any genetic diseases. There are some that can be treated with certain drugs. But for the most part, we’re still in a search for cures for a lot of genetic disorders. It’s like cancer, there’s no cure for that.
X: When you say there’s a tremendous amount of progress, it sounds like you’re talking scientifically. But what about progress in terms of life expectancy, quality of life, and patient prognosis for kids born with this?
JC: That has lagged behind a bit. But we are now at the stage where there are a number of viable treatment options starting to move into the clinic. That’s what’s exciting. It’s taken us a while to get there, that’s for sure. The first challenge was just in finding out what the gene was. Interestingly, the gene that causes muscular dystrophy is called the dystrophin gene. It was cloned in 1988. It was really an amazing feat to pull that gene out.
So that set the field in motion. Suddenly we had a gene. But the problem with these genetic diseases is that you have a very fundamental flaw in every cell of the body. How do you go about fixing that? The way to develop therapies depends on the nature of the gene and what it does. In this case, the dystrophin gene makes a protein that is critical to hold muscle cells together. It’s almost like a girder, a 2-by-4, in terms of holding a house together. When those 2-by-4s start falling apart, the whole house collapses. That’s what you have in muscular dystrophy. The muscles cells form normally, but they’re very fragile, and they break down very easily. It turns out this is a defect that really doesn’t appear to be treatable by any kind of conventional drug therapy, like a nutrient or something to augment a particular pathway inside cells. Instead, you’ve got a fundamental structural problem. People are coming to the consensus that the only way to fix that is to replace the structural defect, to rebuild it.
X: So that led people naturally to gene therapy in the 1990s. What happened? Obviously we don’t see any FDA approved gene therapies.
JC: Gene therapy was an enormous challenge, but things are beginning to fall into place. The problem was that in the early days, people were a bit overly optimistic. There was too much hype. But progress is coming along. We have a mouse model for Duchenne Muscular Dystrophy, and using gene therapy, we are now able to cure those mice. That, in my view, is a major advancement, and we’re getting close to taking this into the clinic.
So there were early setbacks in gene therapy, but things are coming along. It’s a huge challenge to try to replace genes throughout the body. It was going to take longer than we anticipated.
X: OK, but there’s more than one way to try to accomplish this goal of getting the body to start expressing the dystrophin protein. What are some of the best techniques out there that get you excited, besides gene therapy?
JC: I’d say there are five approaches with tremendous potential to have an impact. One is gene therapy. Of the other approaches, the one that’s most developed is the stuff that AVI Biopharma is doing. What they’re trying to do is use small oligonucleotides to manipulate the processing of the dystrophin transcript as it comes off the gene. Basically, the antisense oligonucleotide technology has been shown to … essentially bypass the mutation.
The advantage of that technology is that it can be converted into an ingestible drug. Right now, they’re mostly giving it via injection, either intravenous or intramuscular. It has potential to even be orally administered. It seems simple, it can be given repeatedly, and so far in the animal models, it’s been shown to be fairly effective.
There’s a little bit of safety data now coming out from the human trials [published in The Lancet]. And there was another paper published with a slightly different approach published in the New England Journal of Medicine last year. So it’s showing a lot of promise, and will be an important technology.
There are some limitations to the antisense oligonucleotide technology. One, not every patient will be a candidate for that type of treatment. It depends on what kind of mutation they have. Certain mutations, I don’t think will be correctable. Fortunately, the majority of cases look like they will be treatable with this technology if it works.
The second concern is more of a long range concern that nobody really has answers to. That is, since this drug has a very short half-life. It probably needs to be given every two weeks, or every week, for the rest of the life of the patient. Nobody really knows what the long-term consequences of taking these will be. Will there be off-target effects that start to surface over the years, or will you introduce toxicity, or an immune reaction to [the drug] itself that would limit long-term use? So far, that’s purely a theoretical concern and nobody has seen evidence of that.
X: Can it be delivered throughout the body to every cell?
JC: Mostly, I should say. It appears to be effective when delivered intravenously. They may be able to modify it in pill form. They appear to be effective at getting out of the bloodstream, and penetrating into muscle cells. That was a huge advance.
X: Can you expand a bit on the recent data from AVI? Why do you consider that promising?
JC: It’s just that they had been able to see an effect in humans that mirrored what they had seen in animals. So often with development of therapeutics, you get promising results in a mouse, and then you take it into the clinic and it doesn’t work. What they did was a simple safety study, with an intramuscular injection. What they were able to show, at the injection site, is that they saw restoration of the dystrophin protein coming back on muscle cells. What that says is that the mechanism of action in humans mirrors what we saw in the animal models. That’s a critical step to take, to then go on to develop a delivery mode for whole-body treatment.
X: So they have to go from a single-injection site to a drug that is available throughout the whole body. That’s a big step. Is there anybody further along in trials?
JC: Not with that technology. There is another group doing a slightly different version of the trial. The AVI approach is using morpholinos [a modified antisense oligonucleotide], which I think is going to be the molecule of choice, because they have the longest half-life. Another group [Netherlands-based Prosensa] is using more raw, unprocessed antisense oligonucleotide, and they are a little bit ahead in clinical trials. They published their Phase I trial a year ago, and are gearing up to start their Phase II trial.
They had a publication in the New England Journal of Medicine that was similarly encouraging. They showed they could restore dystrophin.
I have my bias, because the primary approach we work on in this lab is viral vector based gene therapy. But we’re also doing some stem cell work. But in our hands, we can take a mouse model for Duchenne Muscular Dystrophy and give a single injection of our virus, and the mouse is cured for the rest of his life. That’s it, one injection that takes 30 seconds to do, and we have a lifelong cure. We have a dramatic expansion of lifespan in these mice, we treat every single muscle in the body. We completely halt the development of dystrophy, we bring back the sense of normal strength in those mice. Nobody using morpholinos or oligonucleotides has shown anything more than a couple of months of effect. It wears off. They haven’t been able to extend lifespan. They haven’t been able to treat the heart. None of those drugs get into the heart. Our vectors get into the heart very easily.
X: Has anyone shown any commercial interest in taking forward the gene therapy approach?
JC: There is one company in North Carolina (Asklepios) that was formed by a laboratory that’s doing very similar things to what we’re doing here. They’re a competitor of ours, and they raised some money to do a startup to do a Phase I trial of adeno-associated viral vector gene therapy for Duchenne Muscular Dystrophy. They’re starting already, and we’re hot on their heels. We’re going a little slower, because I think we’re focusing a little more on the safety. We saw an immune response to the vector when we tested it in dogs, so we’re testing the idea of temporarily blocking the immune system, and it’s showing tremendous progress.
X: You said the viral vector approach is showing better results in the mice than an antisense oligonucleotide like the one being used by AVI. Why all the excitement about that treatment then, if it’s not getting into the heart, if it’s not lasting more than a couple months, or prolonging lifespan?
JC: I think gene therapy is a more promising approach. But you don’t want to put all your eggs in one basket. It’s important to bring along as many possibilities in the hope that one will get in there and have a major impact on the disease. Second, conceptually, the antisense oligonucleotide approach is very simple. It can be manufactured at hopefully low expenses once you start mass-producing it. It doesn’t seem to require the extensive safety studies you need with gene therapy, because there is fear out there about conventional gene therapy. So it’s a viable approach, and it has shown promise in animals.
X: You’re not a clinician, so you don’t treat patients. What do you consider success five or 10 years down the road for these patients, in terms of life expectancy, quality of life?
JC: It’s always hard to put time frames around things. But I would say with the gene therapy approach that we’re working on here, I look at things through about a 10-year time frame.
I would like to specifically do a few things. One, I’d like to bring back some of the strength, maybe not all the strength. To maintain the ability to walk in young kids. And to have a dramatic expansion of lifespan. That’s what we’re shooting for. I don’t think you’ll ever necessarily have a cure for the disease. A cure to me, is to actually go in and correct the gene and have it be fixed. That’s the ultimate long-range goal for gene therapy.
X: So if your life expectancy is about 30 now, or in your late 20s, how high do you think that can go?
JC: About 10 years ago, the life expectancy was late teens or early 20s. Now we’re starting to push up towards 30.
X: What’s made that difference, given that we don’t have the gene therapy or the antisense that you’re talking about available yet?
JC: Two things. They are actually some simple things, surprisingly. These kids usually die of respiratory failure. So your major breathing muscles, the diaphragm and the intercostals between your ribs, those muscles start failing. Sometimes the breathing rate can plummet during the night because of weakness, and sometimes, the kids will just die from low oxygen. More commonly, what happens is they have a hard time coughing and fighting off respiratory infections. So they’ll get pneumonia and die of that.
So what has gotten around that? One has been putting kids on respirators at night. That appears to be adding years to their lifespan. And more aggressive use of antibiotics once they start developing respiratory infections.
If kids don’t die of respiratory failure, they tend to die of heart failure. People are suddenly coming to that realization—none of these kids used to get referred to cardiologists. It turns out putting them on beta blockers, and some very simple drugs like that to treat heart failure in elderly individuals, can help bring back their heart function. Those two things, if used aggressively, can help these kids live into their 30s.
X: So those are ways of treating some of the downstream symptoms of the disease, and what we’re talking about now with gene therapy and antisense are the first real attempts to affect the underlying gene or protein that’s malfunctioning. You said you expect dramatic improvement, but how much are we really talking about? Will kids with Duchenne ever play basketball or grow up to be active adults, climb mountains, live to be 40 or 50?
JC: It’s hard to say. It will depend on which age you treat them. If you can go in and treat a 2-year-old boy, then I think it’s possible they will never lose their ability to walk. They could be active. I don’t think they’ll climb Mt. Rainier, or be Olympic athletes or things like that. But they can live a normal life, and participate in some sports.
Part of the issue is maintenance of the dystrophin protein, and how much you can get in there. The younger you treat them, the better. The issue you’re dealing with is not having the disease come on in the first place. You can get into a different issue in older kids. The major characteristic of this disease is muscle-wasting. It’s not only that muscles are weak and break down. Muscle tissue is very good at repairing itself. Every time you climb a set of stairs you do some muscle damage, and it repairs itself, with muscle-forming stem cells. What happens with Duchenne boys is that their muscles are breaking down and repairing themselves, breakdown and repair. Eventually this regenerative capacity gives out. It can’t keep up with this ongoing repair. They start losing muscle cells. They get replaced by fat cells, by connective tissue. So the problem is that if you go into a young man that’s 20 years old with Duchenne Muscular Dystrophy, and you do a muscle biopsy and look at it under a microscope, it’s really unusual. Usually, about 90 percent of the volume of the muscle you pull out of a person’s leg is actual muscle tissue. In a 20-year-old Duchenne boy, you may be down to 15 percent of that volume being muscle tissue. The rest is fat or connective tissue. A lot of the weakness comes from the fact that the muscles are just gone. They waste away.
The big limitation with the gene therapy approach we’re working on, is that if we go into a 20-year-old, we can correct and fix all the muscle in the body. But there’s just not a lot of muscle left. We’re not going to make new muscle. My view is that with the older kids, the goal is to stabilize them and prevent any further deterioration and bring back a little strength. That’s true of the antisense oligos, too. The only approach with potential to bring back new muscle is the stem cell therapies, and that’s why muscular dystrophy is one of the leading candidates for stem cell therapy, but that’s lagging a bit behind these other things we’re talking about.
There are a lot of things starting to move into the clinic. Antisense, there’s another drug from PTC Therapeutics drug, there’s gene therapy. Those of us in the field are excited. About 10 years ago, people thought, geez, none of this stuff is ever going to work. Now we’ve got things actually moving into clinical trials.
By posting a comment, you agree to our terms and conditions.