How Fast Can He Run
Six-year-old José Capablanca was excited to see his visitors.
“I think you guys want to know how fast I can run!” he shouted, as he gleefully raced around the living room and kitchen of his family’s home in Gallatin, Tennessee.
José has Duchenne muscular dystrophy (DMD), a rare genetic disorder that affects mainly boys, and which is characterized by progressive muscle weakness, disability and premature death. He also is the fourth patient at Monroe Carell Jr. Children’s Hospital at Vanderbilt to receive a genetic therapy that has transformed his life.
The treatment, called Elevidys, is a single intravenous infusion of millions of gene-bearing viral particles that target skeletal muscle cells throughout the body. Upon receiving their genetic instructions, the cells start making part of a protein called dystrophin that is essential for normal muscle function, and which children with DMD lack.
“It’s not a cure but the next step,” said Jonathan Soslow, MD, MSCI, professor of Pediatrics and director of Pediatric Cardiac Imaging Research. “The hope this treatment brings is incredible — the idea or chance that this can alter the progression of the disease and make a child’s life better.”
“In the younger age group, there’s definitely a clear benefit,” added W. Bryan Burnette, MD, professor of Clinical Pediatrics and interim director of the Division of Pediatric Neurology. “But we don’t know what it’ll look like in 10 or 15 years.”
Burnette and Soslow, who holds the Dr. William R. Long Directorship in Pediatric Research at Vanderbilt University Medical Center, co-lead Monroe Carell’s Pediatric Gene Therapy Workgroup. Their team began offering Elevidys to DMD patients in late 2023, after initial approval by the Food and Drug Administration (FDA).
José received his infusion on June 18, 2024. Prior to treatment, “he had this very wobbly, unsteady gait, like an old man trying to walk,” said nurse practitioner and workgroup member Serena Neumann, MSN, FNP-BC.
“When I get my medicine,” he told Neumann, “I’m going to be big and strong like my dad,” after whom he is named. Within weeks, his movements had become more fluid and coordinated.
“I’m Superman now!” he declared. “I can do anything!”
José’s parents are cautiously optimistic. While the treatment’s long-term effects are unknown, they have no regrets about choosing this chance for him.
José and Stephanie Capablanca praised Monroe Carell’s “awesome” team of health care professionals who made it possible for their son to receive the therapy and who continue to monitor his progress.
“They gave him the ability to be a little boy,” his father said, as he wiped a tear from his eye.
Decades of progress
VUMC has been investigating ways to improve outcomes for DMD patients for decades — long before 1986, when the genetic abnormality that causes the disease was identified.
Gerald Fenichel, MD, professor emeritus of Neurology and Pediatrics at VUMC and founding chair of the Department of Neurology, helped pioneer the management of DMD, trained a generation of clinical researchers, and was a member of the collaborative group that established the efficacy of corticosteroids in slowing disease progression.
“He was a huge influence on my career path,” said Burnette, who graduated from Vanderbilt University School of Medicine in 2001.
When Burnette joined the Vanderbilt faculty in 2007 following his clinical training, there were no FDA-approved therapies for DMD or for another rare and rapidly progressive neuromuscular disease, spinal muscular atrophy (SMA). Until recently, most children with SMA died in infancy from respiratory failure.
SMA is caused by a missing or nonworking gene that normally produces a protein critical for the function and survival of motor nerve cells in the spinal cord. Within two decades of its discovery in the mid-1990s, methods had been developed to repair the defective SMN1 gene or replace it entirely.
Monroe Carell began providing the first in a series of genetic therapies to newborns with SMA in 2016 and currently offers Zolgensma, a gene replacement therapy approved by the FDA in 2019.
“Children who a decade ago would have passed away before their 1st birthday are [today] essentially having normal motor development,” Burnette said. “They’re running, jumping, climbing stairs — doing things that healthy kids do.
“In this population, it’s abundantly clear that the capacity to intervene at the earliest possible stage is having a tremendous impact,” he continued. “It’s probably been seven years since a patient of mine with SMA has passed away.”
Then came Elevidys.
Monroe Carell was a natural fit to offer the new therapy. Its multidisciplinary DMD Clinic, which is co-directed by Burnette, Soslow and pediatric pulmonologist Andrew Sokolow, MD, associate professor of Clinical Pediatrics, is the region’s largest such clinic, drawing patients from throughout the Southeast.
Opening the floodgates
Named for the French physician who first described the condition in 1868, DMD is now known to be caused by genetic mutations that prevent the body from producing adequate amounts of an essential protein called dystrophin.
Dystrophin acts like a molecular “shock absorber” to maintain fiber strength, flexibility and stability in skeletal muscles, including the heart muscle and diaphragm. Without it, every movement causes injury to muscle tissues, leading to irreversible loss of muscle function.
Children with DMD have difficulty walking, climbing stairs and rising from a seated position without assistance. By their early teens, they may require the use of a wheelchair. Despite advanced cardiac and respiratory care, including ventilatory support, few live into their 30s.
In the past 15 years or so, scientists have figured out how to treat rare genetic diseases by packaging corrective genes into harmless adeno-associated viruses (AAVs) and tagging the viruses so they target and unload their genetic cargo into specific nerve or muscle cells.
This is how Zolgensma works. But in the case of DMD, the affected gene is so large that it won’t fit into the AAV vector. Researchers solved this problem by designing a smaller gene that encodes the most important part of the dystrophin protein, a “microdystrophin.”
Much of the early work on gene therapy for DMD was done at Nationwide Children’s Hospital in Columbus, Ohio, under the direction of Jerry Mendell, MD.
Mendell helped pioneer the testing and development of various therapies for DMD, including corticosteroids. He was the first to perform gene therapy for DMD, and he worked with Sarepta Therapeutics, a biopharmaceutical company based in Cambridge, Massachusetts, to develop what would become Elevidys.
The FDA initially approved the drug in June 2023 for ambulatory 4- and 5-year-old patients with a confirmed DMD gene mutation. A year later, the agency expanded the indication to include both ambulatory and nonambulatory patients 4 years old and older. This opened the floodgates.
“We went from having 12 to 15 patients who might be eligible for the treatment to 120 overnight — a tenfold increase in the number of potentially eligible patients,” Burnette said about the impact at Monroe Carell.
By the end of October 2024, six children had received Elevidys at Monroe Carell. A dozen more are in the pipeline. “We’re looking to treat two patients a month,” he said.
One boy’s story
When José was diagnosed with DMD in May 2021, the Capablancas were living in the Miami area with their extended Cuban American families. His great-great-granduncle was the Cuban chess prodigy José Raúl Capablanca, who held the World Chess Championship from 1921 to 1927.
José’s diagnosis, confirmed shortly before his 3rd birthday, was devastating. But it was not a total surprise because his mother is a carrier.
DMD is an X-linked disorder that occurs in 1 of every 3,000 to 5,000 male births.
A woman who carries a gene abnormality associated with DMD on one of her two X chromosomes won’t develop the disease. But since boys inherit one maternal X chromosome (and a paternal Y chromosome), there is a 50/50 chance she’ll pass the mutated gene — and DMD — to her son.
Soon after the diagnosis, José’s physical therapist, Terry Klein, told his parents about a gene therapy for DMD being tested at Nationwide Children’s Hospital in Columbus, Ohio.
While searching online for a pediatric neurologist, they came across Burnette and the DMD Clinic at Monroe Carell.
The Capablancas had lived in Middle Tennessee before. They liked the area, and in October 2021 they moved to Gallatin, 30 miles north of Nashville, with 3-year-old José and his baby sister, Daniella, to be closer to the therapy, whenever it became available.
After testing confirmed he had the mutation that qualified him for the new therapy, José was put on the waiting list. His father’s employer-provided health insurance covered the cost, which for gene therapy can run into the millions of dollars.
Within days after the FDA expanded its approval of Elevidys, José received the treatment. Only one dose is given because the body’s immune system becomes primed to recognize and attack any subsequent infusions of the virus vector.
For two weeks, José endured daily bouts of nausea and vomiting, common side effects of the treatment. But he was a trouper, his mother said. Each time he’d rinse out his mouth and say, “I’m gonna eat now.”
To screen for possible adverse treatment effects on his organs, including his heart and liver, for the first three months José had weekly blood draws and other testing. Eventually the frequency of his appointments will be reduced to once every six to 12 months.
“He has such a positive attitude,” marveled Neumann. “He’s so resilient … and tough.”
Just the beginning
Burnette is amazed at the accelerating pace of new genetic therapies, not only for neuromuscular disorders but for hematologic, metabolic and other diseases that present during childhood. “That’s the world we inhabit now, a completely different universe than it was a decade ago,” he said. “It’s dizzying.”
To offer Elevidys to patients, Monroe Carell had to marshal an extraordinarily broad array of resources and assemble a team of more than 40 specialists, including pediatric cardiologists, neurologists and pulmonologists, pharmacists, nurse managers and nurse practitioners, lab technicians and hospital administrators.
“It’s basically like having an organ transplant,” Burnette said. “It’s almost that level of posttreatment monitoring.”
Burnette credited Monroe Carell’s leadership, including hospital President Meg Rush, MD, MMHC, “for recognizing early that this was going to be important and would probably have a huge impact on how we deliver care, and for recognizing the value to the community of having a program like this.”
He and Soslow are optimistic that the eight-room Pediatric Clinical Research Unit, which is scheduled to open at Monroe Carell this spring, will enable the program to expand its participation in gene therapy clinical trials.
“This is just the beginning,” Burnette said. As the next gene therapies for childhood diseases inch closer toward approval, “we’ve just started marching up the hill.”