The long journey: UC Davis leads the way in muscular dystrophy research and care
Eleven-year-old Jacob Rutt is poised at the starting line for the race of his life – a six-minute walk test. A clinician stands close by and gives him some last-minute coaching.
"When I say go, you’re going to walk as fast as you can to the back cone and then back here, and keep doing that for six minutes."
Jacob nods. He’s done this before. Jacob has Duchenne muscular dystrophy (DMD), the most common and severe form of the muscle-wasting disease. His medical team measures how far he travels.
Though it may seem basic, the six-minute walk provides a wealth of information, measuring Jacob’s endurance, strength, muscle function and gait. The results measure how his muscles are doing.
Developed by UC Davis researchers, the walk test for muscular dystrophy is more than just a measure of muscle function; it’s a measure of hope. The metric has become the gold standard for clinical trials all over the world.
Jacob is enrolled in one of the drug trials and going the distance means he’s holding his ground against a horrible disease.
Proteins gone wrong
Muscular dystrophy (MD) is caused by a defect in a protein – dystrophin. Muscles are frequently injured in normal use, and dystrophin helps protect them. But genetic mutations create damaged proteins. In some forms, such as Becker muscular dystrophy, the protein retains some function. However in DMD, dystrophin is so damaged that cellular quality control systems remove it completely.
Teenager Cody Chaffin has Duchenne muscular dystrophy, the most common and severe form of the muscle-wasting disease. Cody’s mother, Tami Chaffin, is stoic about his condition, but recognizes difficult times are ahead. "We know how this disease goes, at what age this happens or that happens, but each kid is different," says Chaffin. "I want to make sure Cody is comfortable."
When dystrophin is damaged, or eliminated, injured muscle cells die off. Patients develop severe muscle weakness, heart problems and difficulty breathing. Most teens with DMD require wheelchairs for mobility.
"Duchenne patients experience relentless loss of strength and function," says UC Davis’ Craig McDonald, an internationally recognized expert in the clinical management and rehabilitation of neuromuscular diseases. McDonald developed the six-minute walk test. "They fall frequently and lose the ability to walk by 10 to 12. We see the daily progression of weakness these patients experience, and it’s really heart-wrenching."
McDonald has spent his career at UC Davis battling muscular dystrophy. Throughout the past 20 years, he and his team have made major contributions to muscular dystrophy care.
"In the 1960s, kids died in their teens," says McDonald."Now, some patients can live into their 30s, attend college and join the workforce."
Better medications, more sophisticated rehabilitation and therapy and other refinements have all improved MD care. But for McDonald and colleagues the ultimate is to find a cure.
Developing drugs to fix broken dystrophin proteins has been difficult. But on top of that, there have been two main barriers to clinical trials: small patient populations and the right metrics to measure success. Researcher Erik Henricson has helped solve both problems.
"In the late ’90s, no one was doing large-scale Duchenne clinical trials," says Henricson."That was partly because it’s a rare disease and it’s hard to get enough patients for a really good study." Working at the Children’s National Medical Center in Washington, D.C., Henricson helped found the Cooperative International Neuromuscular Research Group (CINRG), a worldwide consortium of researchers intent on finding treatments for DMD and other diseases.
"Duchenne patients experience relentless loss of strength and function. They fall frequently and lose the ability to walk by 10 to 12. We see the daily progression of weakness these patients experience, and it’s really heart-wrenching."
Having multiple centers collaborate on research increased the patient pool. Equally important, standardized protocols ensured that each center performed trials the same way. But there was more to do. Researchers needed measurements to track the effectiveness of new treatments. After being recruited to UC Davis, Henricson worked with McDonald and others to develop the six-minute walk test for patients with muscular dystrophy.
"With a few modifications to help improve child participation, this test was reliable right out of the box," says Henricson."If a kid loses 30 meters on the walk test, that means it’s also harder for him to do everyday things like walk around the block, get on a school bus, or keep up with other kids on the playground. Walking is tied to everyday functions we often take for granted that contribute to overall life satisfaction."
Parents have their own ways to measure DMD progression: How long will my child walk, talk, breathe?
Tami Chaffin’s son Cody is 14 and has Duchenne’s. She is stoic about his condition, but recognizes difficult times are ahead.
"We know how this disease goes, at what age this or that happens, but each kid is different," says Chaffin. "I want to make sure Cody is comfortable. At some point, he won’t be able to communicate or move at all. I’m worried about making the right decisions."
For the Chaffin family, UC Davis has been a godsend, helping them with both the medical and emotional issues.
"They’re such a good staff," says Chaffin. "Everything is intertwined; everyone is involved."
This impact gets multiplied around the world. MD patients who will never set foot in a UC Davis facility are benefiting from the team’s work. Pat Furlong, who lost two children to DMD, is CEO of Parent Project Muscular Dystrophy and values the commitment.
"They have been truly innovative with how they measure the disease, as well as helping the FDA better understand the compounds in clinical studies," says Furlong. "Craig (McDonald) is a great collaborator, giving his time and talent to companies, academic colleagues, patients. We all need to work together and Craig is the symbol for that kind of support."
When CINRG researchers began collaborating on trials, they would test anything that had demonstrated some level of promise.
But now that work has reached a higher level. Investigational drugs designed to correct some of the genetic mutations associated with DMD are in clinical trials and slow the disease’s progress.
In fact, European regulators recently gave the go-ahead to the first-ever drug to combat Duchenne’s. The approval of Translarna was due in part to UC Davis’ six-minute walking test and the team’s analysis of results from clinical trials done here using the drug.
This is where the walk test will tell researchers whether these agents are helping. This and other measurements potentially move life-saving medications to patients sooner.
"Now we have genetic-based treatments on the horizon that target specific mutations and restore protein function," says McDonald. "This is one of the most amazing breakthroughs I have seen in medical science. I think it will lead to historical improvements in care."