UF researchers work to give muscular dystrophy patients longer, fuller lives By Cindy Spence
For fifth-graders, birthdays are big deals, and Sam Hersom is no exception. On July 31, 2012, Sam celebrated his 11th birthday with cake and ice cream, his family and his dog, blowing out candles and enjoying the spotlight.
But that day, Sam also marked a less-joyous milestone. On his 11th birthday, Sam walked for the last time.
Sam has Duchenne muscular dystrophy, a particularly severe variety of muscular dystrophy that affects boys. At diagnosis, a clock starts ticking. As the disease progresses, muscle function deteriorates, leaving most boys in a wheelchair by middle school and struggling to breathe by their 20s. The heart muscle eventually fails and most Duchenne patients do not hit the milestones of manhood: college graduation, a first job, a wedding.
Researchers at the University of Florida can almost hear the ticking, and are working on several fronts to develop new strategies to strengthen their frail patients’ muscles so they can live fuller, longer lives.
There is no cure for Duchenne, but in the last 20 years more therapies have shown promise in preclinical studies, including gene transfer, pharmaceuticals and mixtures of the two. But measuring the effectiveness of these therapies quickly and painlessly in patients has been a challenge, so the Duchenne community is closely watching work by UF researcher Krista Vandenborne and her colleagues.
Typically, measuring the efficacy of an experimental treatment strategy has required painful biopsies that harvest muscle tissue with needles, making some parents and boys reluctant to participate in research, says Vandenborne, chairman of the Department of Physical Therapy in the College of Public Health and Health Professions.
“With surgical biopsies, you’re dealing with a 3-centimeter incision, and it’s very hard for the parents to see that you’re taking a piece of their son’s muscle tissue when you’re dealing with a disease where the primary characteristic is the degeneration of the muscle,” Vandenborne says. “To do that multiple times is extremely challenging, very traumatic for the children and families.”
Other measures are less objective. A 5-year-old boy’s assessment of his strength, for example, can depend on whether he is having a good day or a bad day. As costly as clinical trials can be, objective measures of outcome are crucial, Vandenborne says.
In the study funded by a $7.5 million grant from the National Institutes of Health and in conjunction with Oregon Health and Science University, Children’s Hospital of Philadelphia and the University of Pennsylvania, Vandenborne is investigating magnetic resonance imaging as a measure of therapies. The approach has two key advantages: first, it is painless, and second, it is an objective, repeatable and quantifiable measurement of a boy’s muscle condition.
Using powerful magnets, the MRI machine can create two- or three-dimensional models of the muscles. Normal tissue and damaged tissue give different signals, allowing researchers to assess the severity of muscle damage and changes in it over time.
“There is a lot of excitement in the Duchenne community that several therapeutic strategies have shown a lot of promise in animal models, so there is pressure to move those into clinical trials,” Vandenborne says. “MRI is potentially very attractive because it is a good way to see if these therapies result in a change in the disease progression, without a biopsy.”
“Research into Duchenne is complicated because it is an orphan disease, a rare disease that affects a small population, making it more difficult to get funding and attention.”
— Krista Vandenborne
Vandenborne and her husband, Glenn Walter in the Department of Physiology and Functional Genomics, were recruited to UF in 2001, attracted by the McKnight Brain Institute and UF’s association with the National High Magnetic Field Laboratory. As the biological arm of the magnet lab, UF has some of the nation’s best MRI facilities.
In the ensuing decade, UF’s Duchenne research program has grown to cover every facet — from animal models that Walter studies to clinical trials in the College of Public Health and Health Professions.
In recent years, the muscular dystrophy team at UF has worked closely with pharmaceutical companies to study how drug therapies affect muscle tissue. Barry Byrne, a professor of pediatrics and director of UF’s Powell Gene Therapy Center, was involved in a study that found Cialis, a common erectile dysfunction drug, could help treat Becker muscular dystrophy, and now Byrne and Vandenborne are planning a study to examine how the drug affects muscle in boys with Duchenne, a more severe form of muscular dystrophy.
UF physical therapy research Assistant Professor Sean Forbes is studying whether sildenafil citrate, a similar drug, is therapeutic in animal models of Duchenne.
The UF team also will be monitoring the effect of Eteplirsen, a drug that is being tested in 12 boys nationwide for its potential to increase the function of dystrophin proteins that are key to muscle fiber and health. MRI data will help determine whether the experimental drug treatment works.
Vandenborne says research into Duchenne is complicated because it is an orphan disease, a rare disease that affects a small population, making it more difficult to get funding and attention. Duchenne is caused by a defective gene for a muscle protein called dystrophin and is diagnosed in one in 3,500 male children. While that is a lot of boys, research subjects are not as easy to find as in a study, for example, of diabetes.
“In the Gainesville community, there might be five children with Duchenne,” Vandenborne says. “You can’t run a clinical trial with such small numbers, so we are very aggressive in recruitment.”
Two years into the study, Vandenborne says 140 children are enrolled in the imaging study, some coming from as far away as Spain and Canada to participate.
For the Hersom family, the trip is short. Sam’s dad, Matt Hersom, is a faculty member at UF, and the two have turned the MRI sessions into father-son outings, sometimes with ice cream on the way home to Newberry.
Sam watches a movie while inside the magnet and Matt heads down the hall to do questionnaires with researcher Roxanna Bendixen, who is assessing quality of life issues in Duchenne families. Bendixen asked Vandenborne to be her mentor on her NIH career development grant, and has spent the last two summers working at NIH. In a second grant, Bendixen is examining social networks of boys with Duchenne.
For boys, not being able to participate in physical activities can be socially isolating, Bendixen says, so she is interested in families’ coping strategies.
“I want to know why parents choose to do things or not do things,” says Bendixen, a research assistant professor in the Department of Occupational Therapy. “Sometimes it’s as simple as ‘Do you have to go up stairs?’ Theme parks can be accommodating, but sometimes you can’t get into a convenience store because of a curb.”
School experiences, too, are part of Bendixen’s investigation. She wants to know how parents, students and teachers communicate about the disability. Some teachers encourage the boys to participate but others fear injury and become overprotective, she says. One family opted to homeschool after their son was bullied. By middle school, using the restroom becomes an issue, especially if there are two or three stairs to navigate or if a boy needs the teacher’s assistance. Parents report boys going all day without a bathroom break because they are embarrassed to ask for help, Bendixen says, adding “Those stories always break my heart.”
“In late elementary and early middle school, a boy might still have the ability to walk a little, but might be afraid of being knocked down and not being able to get back up. One of the first things these boys lose is the ability to get up from the floor, so they have a scooter,” Bendixen says, “but often you will have a group of kids who will come to their aid.”
For Sam, school is great. He attends Oakview Middle School with many children he has known since kindergarten. Matt says crossing campus with Sam is heartening: “Everybody is saying ‘Hi Sam, hi Sam.’”
Sam smiles shyly, but admits, “I’ve got a lot of friends.”
The Hersoms try to educate Sam’s class each year. One year, the teacher suggested the kids try walking in her husband’s firefighter boots to get an idea of Sam’s experience. One boy thought it would be no big deal, until he tried it.
“The whole rest of the year, that kid was Sam’s biggest bodyguard,” says Kris Hersom, Sam’s mom. “He realized how hard it was for Sam to move around.”
The Hersom family is like many Duchenne families in another important way, Bendixen says.
“The family unit becomes really close, they do everything together and have a lot of special time they spend at home together and have wonderful family traditions. An older son who doesn’t have Duchenne may have a ton of friends, but he knows that Friday night is family pizza night and that will never change.”
Sequestering Sam isn’t an option for the Hersoms, Kris says, because it would waste the time he has. Doctors were optimistic when Sam was diagnosed 10 years ago, thinking a cure was right around the corner. Now, she says, they participate in research knowing that many of the new therapies will not help Sam.
Donovan Lott, a research assistant professor of physical therapy, says 26 years have passed since the discovery of the genetic defect that causes Duchenne, about the lifespan of a boy diagnosed then. The cure has eluded researchers, but therapies have allowed more boys with Duchenne to grow into men, he says, and he is interested in a therapy that seems counterintuitive: exercise. The MRI studies, he hopes, will allow him to answer a question boys and parents always ask: Is exercise good or bad for boys with Duchenne?
The muscle cell in a boy with Duchenne is much more fragile than in a healthy boy, putting many athletic activities off limits. As the muscle cells deteriorate, they are replaced with fat cells that don’t provide support. What hasn’t been studied is whether there is a level of activity that would be therapeutic. Pushing too hard can cause injury, but not exercising enough can cause more atrophy and waste in the muscle.
Lott says he knows parents who limit how many steps their son takes each day; others want their son to run and play as much as possible.
“Parents want to know, ‘What can my child do?’ I can’t tell them what the science says because the science is not out there. We need to figure this out,” Lott says.
In Becker muscular dystrophy, similar to Duchenne but not as severe, adults in a cycling program improved strength and muscle function.
Lott is collaborating with Vandenborne to determine how the amount of muscle damage relates to the amount of activity a child does at home. Each boy wears an accelerometer 10 hours a day for a week, then mails it back to Lott. The device records a step count and other measures of energy expenditure and also allows Lott to see the amount of time the boy spends in activities from sedentary to maximum intensity. Lott hopes to follow that study with another in which an exercise chair and a laptop form a home exercise station that could be monitored from campus, allowing researchers to follow the boys’ exercise sessions.
MRI would be used to assess the muscles to determine if the exercises remain safe as they increase in intensity, Lott says. The boys also would be asked to rate any pain.
“If we are able to do an exercise, and it shows we can do it safely but it didn’t have enough impact, that in itself is a good finding. If it’s safe, is there something more we can do since we know it’s not causing harm,” Lott says.
Lott says the Duchenne research at Florida is making a splash, and Vandenborne credits the pipeline UF has built for Duchenne work. For research to move forward, she says, a critical mass of people is needed to create the next generation of scientists, and Duchenne work at UF includes senior faculty, junior faculty, pre- and post-doctoral researchers, even undergraduate students.
The boys become part of an extended research family, the scientists say. Bendixen spoke to Sam’s class at school, Matt Hersom joined Lott in a series of awareness sessions at fraternities. Vandenborne’s and Lott’s sons both served as healthy control subjects for the research. They exchange holiday cards and remember birthdays. Especially the birthdays.
“On the 15 occasions Matt and I lectured together, I would hear him say, ‘I’m going to bury my son.’ That’s a hard concept to know ahead of time; most parents don’t have that,” says Lott, a father himself. “It does put an urgency into our research. He and his wife have both commented that birthdays are great celebrations, but sad as well because it’s one more birthday closer.”