Two UCLA medical researchers are engaged in a very personal fight against a lethal genetic illness that affects one in every 3,500 boys. Their Center for Duchenne Muscular Dystrophy is leading the effort to find treatments and extend lives — including that of their son.
|The work of Drs. Stanley F. Nelson (left) and M. Carrie Miceli (right) to find improved treatments for boys with Duchenne muscular dystrophy may one day help their own son Dylan (second from left), pictured along with big brother Calvin.|
By Shari Roan, Photography by Ann Johannson
Dylan Miceli-Nelson, 12, has just gotten a new Xbox One, and it wouldn’t be wise to enter the Miceli-Nelson home these days without preparing for a game of Just Dance 2014 or Call of Duty: Ghosts. He is standing in front of a big-screen television, game controller in hand. His parents, Stanley F. Nelson, MD, a former pediatric oncologist and now a UCLA professor of human genetics, and M. Carrie Miceli, PhD, a UCLA professor of microbiology, immunology and molecular genetics, try to psyche themselves up for a game of Just Dance. Dylan and his brother, Calvin, a junior in college, are ready to bust a move. “I like to dance,” says Dylan, who has a mop of thick brown hair, dimples and an irrepressibly joyful attitude. “But I don’t like to dance in public. I like pop, rock ‘n’ roll — ’80s — hip hop, rap and electric.” Drs. Nelson and Miceli sigh, get up from the couch and join in the dance. There’s no way they’re getting out of it.
To say these two parents would do anything for their funny and exuberant son is an understatement. Besides dancing when called upon and fulfilling their parental duties of seeing to homework, teeth brushing and proper use of the English language, Drs. Nelson and Miceli have rerouted their careers to help beat back a disease that afflicts Dylan and one of every 3,500 boys worldwide.
As a toddler, Dylan was diagnosed with Duchenne muscular dystrophy (DMD), the most common fatal genetic disease of childhood. Mutations in the Duchenne gene, which is on the X chromosome (thus affecting only boys), impair production of the protein dystrophin, which is required for healthy muscle function. Boys with Duchenne typically lose their ability to walk by adolescence and go on to experience respiratory and cardiac failure. Life expectancy is about 25 years of age.
But things are changing in the world of those affected by Duchenne. The first prescription medication specifically to treat the disease may be approved by the U.S. Food and Drug Administration (FDA) this year. Other novel therapies are in the works. In Southern California, thanks to Drs. Nelson, Miceli and their UCLA colleagues, boys with Duchenne now have access to state-of-the-art care and can enroll in one of several promising clinical trials. Drs. Nelson and Miceli have not only emerged as leading scientists in the field, they also have rallied a far-reaching network of other UCLA scientists, students and community members to work on all aspects of the disease and those affected by it.
|Mutations in the Duchenne gene, which is on the X chromosome (thus affecting only boys), impair production of the protein dystrophin, which is required for healthy muscle function.|
Among DMD researchers and clinicians nationwide, UCLA is known as a dynamic place that has achieved a lot in a short amount of time, says Jeffrey Chamberlain, PhD, McCaw Chair in Muscular Dystrophy at the University of Washington and co-editor of Duchenne Muscular Dystrophy: Advances in Therapeutics. “Their reputation is one of being very-high-quality scientists who are taking a broad approach to muscular-dystrophy research,” he says. “Often at universities, you have one, two or three labs working on muscular dystrophy and being very specialized. UCLA has established a fabulous link between basic research and clinical application.”
Drs. Nelson and Miceli’s colleagues on campus would agree. “Stan and Carrie helped galvanize things on campus,” says Melissa Spencer, PhD, professor of neurology and one of the few Duchenne researchers at UCLA when Dylan was diagnosed. “It has brought in people who weren’t working on Duchenne before, new ideas, new motivation. Now we have the clinical mission, research mission, education mission and community-outreach mission. The breadth of what we’re doing goes beyond the science.” That’s where Dylan, other local boys with Duchenne and their families come in. As it turns out, love has a place in science. “Dylan is very funny,” notes Dr. Spencer, who is co-director, with Drs. Nelson and Miceli, of the Center for Duchenne Muscular Dystrophy at UCLA. “He’s a character. He’s very entertaining and fun to talk to. He’s full of love, too.” Although he forbids his parents to talk shop at the dinner table, Dylan participates in several clinical trials and is good-natured about his doctor visits. In addition to aspiring to become a video-game designer, toy designer, app designer and artist, he recently shared this with his dad: “I want to be the bravest disabled guy in the world.”
SCIENCE IS A ROCKY ROAD. For every small success, there are seemingly endless failures. Questions overwhelm answers. Months can go by without a single sign of progress. Researchers cannot afford to get too emotionally invested in the day-to-day stuff. That is the tricky balance required of Drs. Nelson and Miceli.
Even before he was diagnosed, they suspected Dylan had the disease. His gait was unusual, and he tended to walk on his toes. Still, the diagnosis was devastating. The couple made an appointment to speak with Dr. Spencer.
“I knew at the time there was nothing to be done,” aside from giving a child steroids to help prolong the ability to walk for two or three years, says Dr. Spencer. “I prepared a notebook for them with papers on the disease. It wasn’t much, but it was all I could do. I was heartbroken for them.”
The notebook revealed that, since the gene for the disease had been discovered in 1986, important research had been completed that was poised for translation into clinical use; however, in many clinics, very little had changed to improve the boys’ quality of life or life expectancy. “Back when Dylan was diagnosed, often the first message parents would hear in the clinic was that this is a fatal disease,” Dr. Nelson says. “Doctors would say, ‘Take your son home and love him’ — the implicit message being that the medical system had nothing to offer. But the medical system actually has quite a lot to offer. That’s what we’ve been helping to set up at UCLA.”
The Center for Duchenne Muscular Dystrophy at UCLA was established in 2006 to build a multidepartmental program performing basic research and to translate that research into clinical care. The center also worked to establish a multidisciplinary care clinic to provide care for an estimated 600 Southern California boys with the disease. With support from the center, Perry Shieh, MD, PhD, associate professor of neurology and neuromuscular medicine, and his colleagues established the Pediatric Neuromuscular Clinic. Before the clinic’s opening, many patients, such as Dylan, traveled out of state to receive specialized care. The clinic is also credentialed with California Children’s Service, which allows boys from families on MediCal to access its many services. “It’s a fully coordinated clinic,” says Nancy Halnon, MD, associate professor of pediatric cardiology and the center’s clinical liaison, who is a leading physician for Duchenne care. “Duchenne is a complicated disease. Kids have to see multiple specialists. It’s burdensome for a family to try to arrange six different physician visits with six different specialists. Having everyone in one place is good for a matter of convenience, but it’s also good to keep track of how these kids are doing.” The clinic offers extra services, such as psychosocial care that helps patients and families understand and cope with the disease. Patients can also opt for enrollment in Duchenne clinical trials, the number of which has exploded in recent years. “We’re a go-to site now,” Dr. Miceli says. “We’ve got the population. We’ve got the expertise. We didn’t have those before.” “Most patients don’t know what clinical trials are occurring in Southern California,” Dr. Nelson adds. “They’re disconnected from the academic. Our goal, and our hope, is to get every single boy with Duchenne on a clinical trial and on multiple clinical trials during his life to try to move the ball forward as fast as possible.”
Top: Skin cells of a DMD patient are reprogrammed into muscle cells in culture for drug screening.
Bottom: A muscle crosssection
from a DMD mouse
showing rescued dystrophin
expression after exon
skipping. The green stains
the dystrophin protein that
is otherwise missing in DMD
mice. Blue is the cell nucleus.
WHILE NATIONWIDE, ONLY ABOUT 5 PERCENT OF BOYS WITH DUCHENNE participate in a clinical trial, about 50 percent of UCLA’s 80 patients are enrolled in research. And while participation is often motivated by altruism, today there is well-founded hope that some of the ongoing later-stage clinical trials will produce meaningful benefits. The greatest excitement lies in a novel strategy that reflects a sophisticated understanding of the molecular genetics of the disease and addresses the underlying pathology: the disruption of the protein dystrophin. Several major drug companies are testing protein-replacement strategies that involve tricking muscle cells to produce dystrophin by forcing the skipping of portions of the gene, called exons, which are adjacent to the missing or faulty regions. Exons are the protein-coding portions of genes, and faulty exons can make a once-readable genetic instruction unintelligible. The investigational drugs use small pieces of DNA called antisense oligonucleotides to act as molecular patches that allow the gene to be “read” and thus produce dystrophin. It’s too early to tell if exon skipping will work. Last fall, the maker of one experimental medication called drisapersen announced that boys taking the medication fared no better than those taking a placebo medication in a phase 3 clinical trial. Meanwhile, a drug called eteplirsen has shown promising results in a phase 2 trial of 12 boys. Boys taking the medication have shown a stabilization of their walking ability compared to boys on a placebo drug. (A walking test is the way the drugs are assessed for efficacy.) When those patients on the placebo were switched to eteplirsen, however, they showed stabilization in their walking ability. Moreover, muscle biopsies showed increased dystrophin. Both companies are in active discussions with the FDA.
“We don’t honestly know whether it’s working, but the data are very encouraging,” Dr. Nelson says. “These boys have now been on the drug for two years, and they produce some dystrophin. Before they made no dystrophin. That’s amazing in itself. This all shows the strategy is a good one.”
Researchers are also learning more about the biology of the disease, Dr. Miceli adds. This information may lead to therapies to manage or modify various symptoms, such as the fibrosis, or scarring, that develops in muscles as a result of the disease. Another strategy focuses on repurposing FDA-approved medications to treat Duchenne. For example, one clinical trial involves using tadalafil, a medication for erectile dysfunction, in patients with muscular dystrophy to relax the blood vessels in muscles during exercise.
At UCLA, Drs. Nelson, Miceli and Spencer are developing strategies to enhance exon skipping using FDA-approved medications. Using the high-through-put molecular-screening technology available at UCLA — which allows researchers to quickly examine thousands of small molecules — they found about 20 drugs that appear to make exon skipping more efficient. One medication, called dantrolene, is particularly promising. Developed about 50 years ago, dantrolene relieves muscle contractions caused by an adverse reaction to anesthesia, but the UCLA research team has found an exciting new use for the drug. In December 2012, a study by Drs. Miceli, Nelson and Spencer appeared in the journal Science Translational Medicine, demonstrating that dantrolene can enhance exon skipping in mouse models and that mice make more dystrophin and have improved muscle function. Their study also showed that dantrolene enhances exon skipping in cultured muscle cells from DMD patients. These human-cell-line experiments open the possibility that dantrolene might improve the efficacy of oligonucleotides currently being tested in the clinic. In 2012, these researchers at UCLA received a grant from the California Institute for Regenerative Medicine to study drug-combination therapies aimed at restoring dystrophin in mouse and human DMD models.
SUCH SUCCESS IS ATTRIBUTED TO THE COLLABORATIONS that Drs. Nelson, Miceli and Spencer helped to initiate. Dr. Miceli’s lab has also been working with others to collect skin cells from Duchenne patients that can then be turned into muscle cells in the lab in order to screen drugs more effectively. During this project, researchers must note the precise genetic mutation in each boy’s cells — there are many types of Duchenne mutations — in order to see which drugs work best on various specific mutations. The research reflects the need to personalize medical therapies.
Top: Dr. Melissa Spencer was one of
the few DMD researchers at UCLA
when Drs. Stanley F. Nelson and
M. Carrie Miceli brought their son
Dylan to her. Now she collaborates
with them as co-director of the
Center for Duchenne Muscular
Dystrophy at UCLA.
Bottom: Dr. Rachelle Crosbie-Watson, education liaison for the
Center for Duchenne Muscular
Dystrophy at UCLA, created an
undergraduate course, Molecular
Mechanisms and Therapies
for Muscular Dystrophy, to
give students a taste of how
translational medicine can work.
Dr. Nelson and fellow researchers, meanwhile, are looking at patients with the same genetic mutations but who show variations in disease progression. It’s likely that there are other genes involved in Duchenne that modify disease progress and that could be targets for new therapies. Multiple research collaborations are now ongoing among researchers in disparate fields who, prior to the development of the center, didn’t even know each other. The center has handed out several seed grants on campus to encourage novel research on Duchenne. “At UCLA, everyone was working within individual silos,” says Rachelle Crosbie- Watson, PhD, professor in integrative biology and physiology and neurology, who serves as education liaison for the center. “There were several musculardystrophy researchers on campus and we talked to one another, but we weren’t collaborating with each other. That is what Stan and Carrie brought to the table. They’ve connected us.”
For instance, Dr. Spencer has been studying the role of osteopontin, a potent modulator of inflammation and fibrosis, as a new target for the treatment of Duchenne. “Having Carrie, an immunologist, come in and collaborate with us was huge,” Dr. Spencer says. “I bring the muscle perspective and she brings the immune perspective.”
Thirteen labs at UCLA are now working on aspects of the disease. “We’ve got this team that’s very diverse,” Dr. Miceli says. “Nobody in the room has the same skill set. That’s when you get this kind of synergy of talents that really drives a field that had really been quite insular before. Now it’s a paradigm for how you take a rare disease from genetic discovery into the clinic.”
Adds Dr. Nelson: “We think the Center for Duchenne Muscular Dystrophy is the right model for how you tackle rare diseases. You have to take this team-science approach and team-clinical approach, and those two things have to work well together to generate new ideas and new knowledge with an eye toward biotech.”
It’s not surprising that Drs. Nelson and Miceli would think about how the UCLA model might also serve people with other types of rare disorders. Despite Dylan’s diagnosis, they have always looked beyond their specific circumstances. “They are just truly good people,” Dr. Spencer says. “They’re not selfish. They are cautious about not making this only about their son. It’s very admirable. That’s not easy to do, and I think that they have to work at that every day.”
TAKING THE BROAD VIEW means that the Center for Duchenne Muscular Dystrophy also assists with fundraising for research, community outreach, education and training. A few years ago, Dr. Crosbie-Watson created an undergraduate course, entitled Molecular Mechanisms and Therapies for Muscular Dystrophy, to give students a taste of how translational medicine can work. Over 10 weeks, students hear lectures from scientists, physicians, physical therapists, parents, patients and members of advocacy organizations.
“We are changing undergraduate education in a phenomenal way,” Dr. Miceli says. “Instead of doing things superficially, you take one subject and do it deeply. You teach the process better.”
The course earned Dr. Crosbie-Watson the UCLA Academic Senate Distinguished Teaching Award in 2013. Students also formed a student group, Bruin Allies for Duchenne — otherwise known as the BADAsses — to foster awareness of the disease. The group has held a campus screening of a 2013 documentary, Dusty’s Trail: Summit of Borneo, about a group of people who climb a mountain in Borneo to raise awareness of the disease — the film’s producer is the mother of a son with Duchenne — and sponsored an information booth during UCLA’s Disability History and Awareness Week.
|Dylan, with his service-dog Kong, recently told his father, “I want to be the bravest disabled guy in the world.”|
“They’ve experienced the revolution that’s going on in Duchenne research,” Dr. Crosbie-Watson says. “They come out completely changed. One of my students said, ‘This course has changed my life.’ They realize what it means to have a disability, what life is like in a wheelchair. They become miniactivists.”
Despite the enormous growth in clinical care, research and community outreach achieved at UCLA over the past five years, Dr. Nelson says, “We don’t feel like we’re anywhere close to being done. We are not satisfied.” Still, he and Dr. Miceli work hard at balancing their lives as scientists with their role as parents.
“It is a struggle. We set a priority to always be home for dinner,” Dr. Nelson says. “One of the hard parts about the disease is that it’s on a relentlessly progressive course. Dylan’s needs are going to increase over time. We’re well aware of that. We feel we’ve gotten the luxury and ability to focus as much as we can on research and get as much done as we can right now. And then we realize that Dylan’s needs will change over time.”
“I learn a lot from them,” Dr. Crosbie-Watson notes. “I learn about what’s important in life. I learn about commitment to a cause. Research isn’t easy. There are huge disappointments. They provide a lot of hope and motivation to keep moving forward.” Dylan is a recipient of that hope. Over time, his parents have helped him understand the disease and that they are working on therapies to treat boys like him. “It gives him hope and makes him feel he is part of that process,” Dr. Miceli says. “We’re not the ones to say, ‘We’re finding a cure for you, sweetheart.’ That’s not what we do. We’ve never made those promises, and we never will. But he does like to think that the field is advancing and that we are all helping with that.” Dylan doesn’t even mind hanging around his parents’ labs on occasion. “I think it’s helpful — what they’re doing,” he says. “They’re helping kids. If no one was working on it, that wouldn’t be good.”
|“One of the hardparts about the disease is that it’s on a relentlessly progressive course.”|
He has become keenly interested in disability rights and is proud to show off his service dog, Kong, a golden retriever/lab mix whose specialty is providing affection. Dylan can still walk around the house, although he uses a scooter outside the home. Still, just like his parents, he has the ability to seize the moment and make the most out of any situation. He describes how impressed he was with a buddy after the two recently conducted an outdoor race, his friend on foot and Dylan on his scooter. “He beat me,” Dylan says, with a grin. “And I pretty much go full speed.”
Shari Roan first wrote about Drs. Stanley F. Nelson and M. Carrie Miceli and their son Dylan for the Los Angeles Times in 2010. For more information about the Center for Duchenne Muscular Dystrophy at UCLA, go to: cdmd.ucla.edu