Lifewatch: Muscular dystrophy band-aid

Reported by Claire Hosmann - bio|email
Posted by Debra Worley - email

(WECT) - One in every 3,500 baby boys is diagnosed with muscular dystrophy, one of the most common genetic disorders.

The most devastating form of the disorder slowly robs kids of their muscles, and they rarely live past age 20.

Drew Bonner is an inspiration to kids with duchenne muscular dystrophy.  While his muscles are getting weaker, his determination is stronger than ever.

"It's a challenge I have to overcome," said Bonner.  "It's one more hurdle to jump over."

Researchers say they've cleared a huge hurdle in finding a treatment.

"It's at our fingertips, getting these kids out of their wheelchairs," said professor of pediatrics Dr. Eric Hoffman.

Dr. Hoffman is part of a world-wide team developing the technique called "exon-skipping."  The injectable drug cocktail works like a band-aid, covering up the mutation that causes muscle weakness, allowing cells to make a healthier protein that improves muscle function.

"It's almost if you were reading a recipe and instead of putting salt, your mutation said put in lots of hot pepper instead," said Dr. Hoffman.  "Well, your cake wouldn't be so great. This band-aid lets it skip over that wrong pepper instruction."

When tested in dogs with muscular dystrophy, the animals went from struggling to walk to running.  The canine version of the disease affects the same gene as the human version.

Researchers say this strategy could help up to 90% of people affected by duchenne muscular dystrophy.

Trials involving people are now underway in Europe.

Below is an in-depth interview with Dr. Hoffman.

Eric Hoffman, M.D., Director of the Research Center for Genetic Medicine at Children's National Medical Center in Washington, D.C., explains how a drug discovery may stop the most common type of muscular dystrophy in its tracks.

What is your research project into muscular dystrophy about?

Dr. Hoffman: This was a collaboration with the National Center of Neurology and Psychiatry in Japan. It's the first type of therapeutics that has helped a large animal with a similar disease as muscular dystrophy. Many pets and animals have a disorder similar to the Duchenne muscular dystrophy that humans get. Years ago, an owner brought in this one dog that we showed had the same type of disease as these children. For the last 20 years, we've been trying to develop new ways to treat that dog, and this is the first success, which bodes very well for human trials.

How successful was the treatment?

Dr. Hoffman: We took littermates, or siblings of dogs, that were affected and unaffected with muscular dystrophy, and then used an intravenous injection of a very customized personalized type of medicine called a morpholino -- it's almost like a band-aid over the dog's problem with the gene or the mutation -- to get the dog's cells or its muscles to skip over the mutation and as a result repair the gene and make new protein to save the muscle, and that worked.

What did the research show?

Dr. Hoffman: The one dog who started off as more severe and could just barely walk, once we injected the drug, he was able to start running and do much better than his sibling. Using any criteria -- whether it's how their muscles are functioning or what the muscle looks like; MRI, magnetic resonance imaging; how they eat; any criteria we use -- the drug treatment significantly helped the dogs.

How significant is the progress the dogs made?

Dr. Hoffman: It seems to be that the drug treatment, over just a matter of weeks, or a few months, helped the dogs quite a bit, and we really have a lot of hope that the drugs will do the same thing in humans. There are some other significant parts of this story -- this type of personalized medicine or morpholino, it's called, it's really sort of the first proof of principle in terms of a whole organism or whole dog, and it bodes well for many other types of therapies, for other genetic diseases, and even for cancer. If this is working as it is in muscular dystrophy, we think the same approach can then be applied to many other disorders.

Is this approach designed specifically with the genetic makeup of that individual?

Dr. Hoffman: The way the drug works -- it has a specific DNA sequence, so we can target it to a very small region. There are three billion letters in the human genome, and we take just 20 of those next to each other and we design a drug that goes and attaches to that region. It can either turn on or turn off the gene that it's attaching to -- in this case, in the dogs, we're actually turning it on, but in many things like cancer, you'd want to turn off genes that are causing cancer. Our ability to just use an IV injection and get that sequence specific sort of designer drug throughout the body, it's the first time that that's been achieved in a large animal.

How does the IV injection work?

Dr. Hoffman: An analogy is that the gene that causes muscular dystrophy is like a very large recipe in the Joy of Cooking. In fact, the typical Joy of Cooking recipe is like a gene with about 30,000 letters. This one has about two-and-a-half million letters, so it's a very large recipe. A mutation is anything that destroys the gene in some way, so it hurts it so you can no longer read the recipe and make the appropriate thing. This drug acts as sort of a patch or a band-aid -- it lets the gene just sort of miss that part and still make the correct thing. It's almost like if you were reading a recipe and instead of putting salt, the mutation decided to put in lots of hot pepper instead. Well, your cake wouldn't be so great. This band-aid lets it skip over that wrong pepper instruction and you still make a cake. Well, it's a cake without a little salt, but that tastes pretty good and still works as a cake. It skips over that crucial part, and so in this case, not having the hot pepper is better than not having salt.

How challenging is it to be diagnosed with Duchenne muscular dystrophy?

Dr. Hoffman: Duchenne muscular dystrophy is the most common genetic disease worldwide. The reason it's so common and it affects all populations is that it's such a large recipe, so it's so easy to mess it up through mutation or some random events. The other thing is, even though it's a genetic disease, most cases don't have a family history, so it just appears in anybody's family at an equal rate pretty much. Because of that, the nature of the disease is very devastating in that children are born normal, but then show weakness around kindergarten or first grade, and then lose gradually over the next 10 or 20 years most of the muscles in their body. It's both common and devastating, affects all world populations, and while it's genetic, it doesn't really run in families. This has been a big target in studies, to try to both understand what causes the disease and try to develop therapeutics. 20 years ago was the first cloning of the human disease gene, and Duchenne muscular dystrophy was the first gene. It was the target of trying to use the human genome to understand diseases we had no idea what was causing them, so it's nice 20 years later to see it's finally translating; that genomics increases in knowledge lead to therapeutics.

Is Duchenne muscular dystrophy a fatal disease?

Dr. Hoffman: Traditionally, patients die by the time they're 20. Ventilator support and steroids have extended their life span, but many patients who are now alive in their 20's and 30's have relatively little use of their muscles. Fortunately, their speaking is spared, and some muscles like their eyes are spared to some extent, but it's a very debilitating disorder.

How will this exciting discovery be applied to humans?

Dr. Hoffman: This paper that we published really strongly argues that this will work in humans, that this is directly translatable to most Duchenne patients and we will make them better in the near future. That said, it's also very different from other drugs. There are many challenges in going through regulatory procedures. The whole nature of a customized drug is something that nobody has really dealt with before, so there are a lot of very challenging hurdles, not only regulatory, but even marketing -- how do you market a drug where everybody might have a different drug? Can you really go through all the FDA regulatory hurdles for each patient? Now, it's really not that bad - there are whole groups of patients that have similar mutations, but in the end, this will involve many, many different drugs to be able to treat the majority of patients. That's what we're approaching now, how to get through the regulatory hurdles and bring this to patients and not let just rules and regulations stand in the way of helping these boys at the same time. Part of the newness is also making sure it's safe, and so far, it's safe to these dogs, but it was just three dogs. We clearly want to make sure that it's safe for patients before we start injecting everybody with customized band-aids.

How is testing in dogs different than testing things in laboratory mice or rats?

Dr. Hoffman: I think the fact that we were able to treat the dogs is significant compared to many experiments in mice. It's often said that mice were cured of cancer years ago, and translating that to human patients has just been challenging and hard. I think dogs are much more similar to humans and have many of the same challenges. If you can overcome those challenges in a dog, it seems it's much closer to doing the same in humans.

When will human trials begin?

Dr. Hoffman: There are some limited human trials already underway. There's a company called Prosensa in Holland that has done some intra-muscular injections and published that about a year ago on just four patients, and showed just a small injection into the muscle seemed to be working. Francesca Montone in England has been working with a company called AVI in the U.S. to also start similar dose ranging studies. There's been no real proof of principle in the sense of patients that have been shown to get better yet, but clearly, we have to get more patients tested with higher levels of drugs and start overcoming these barriers to bringing this to children.

What does this development mean to you -- to someone who is immersed in this research all the time? What do you think this means for the muscular dystrophy community to have something like this on the horizon?

Dr. Hoffman: Twenty years ago, the Duchenne muscular dystrophy gene was the first gene identified of the human genome, and there was so much hope back then of myself and everybody that this could immediately be transitioned to getting kids out of their wheelchairs. It's been a very long 20 years, and in many respects, I think I share the sentiments of the parents. To finally now feel that it is tangible, it is at our fingertips, getting these kids out of their wheelchairs, to me, that is really finally coming full circle. The hope that genomics initially presented was just more challenging to fulfill.

Is Duchenne muscular dystrophy a specific type of muscular dystrophy?

Dr. Hoffman: Duchenne muscular dystrophy is the most common type of neuromuscular disorder. There are about 40 different neuromuscular disorders, including things like ALS disorders, but Duchenne is generally considered the most common worldwide and also one of the more severe.

How long did the study last?

Dr. Hoffman: The study took about three years. One of the unique aspects of the study is how internationally and nationally collaborative it was. It involved contributions from the National Institutes of Health, six different centers in the United States, and the Japanese government, as well as many foundations including the Foundation to Eradicate Duchenne. There were many people working together in this very difficult study and very expensive study, to show that this was possible, that we could actually help these dogs and the implications for humans.

Each of these dogs that we treated for four to six months cost about $200,000 to $300,000 just in drug costs. Clearly, this presents a problem. We have to bring the cost down before we can deliver this effectively to many patients, but there are already plans for the large-scale production and to then bring that cost substantially down.

If you would like more information, please contact:
Genetic Counseling
Children's National Medical Center
(202) 476-4925