AVI Offers Glimmer of Hope for Muscular Dystrophy, Says UW Neuroscientist Jeff Chamberlain

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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.

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