Children with Duchenne muscular dystrophy (DMD) require lifelong care, with progressive muscle weakness and degeneration that leads to premature death, often by a patient’s 20s or 30s. Pediatric neurologists at Children’s Health℠ and UT Southwestern, are working to change that.
Together, we’re researching innovative DMD treatments that can potentially improve symptoms and life expectancy. These therapies aim to counteract muscle degeneration by addressing its various effects, including weakness, deterioration, fibrosis and impaired ability to regenerate.
“We’re involved in the latest research on gene replacement therapy, exon-skipping therapies, steroid alternatives and allogeneic cardiosphere-derived cell therapy for DMD,” says Kaitlin Young Batley, M.D., Pediatric Neurologist and Assistant Professor at UT Southwestern. “In the future, I hope we will be able to create personalized treatment plans for each patient, potentially even combining medications to treat their unique set of symptoms.”
Dystrophin restoration through exon-skipping therapies
DMD occurs when mutations in the DMD gene prevent the body from producing dystrophin, a protein essential for muscle development. The lack of dystrophin causes muscle degeneration that typically begins in the limbs and eventually involves cardiac and respiratory muscles, leading to life-threatening complications and, ultimately, early death.
DMD gene mutations are most commonly due to deletions of portions of the gene, called exons. Exon-skipping therapies are a class of RNA-based medications that use antisense oligonucleotides as molecular “patches” to skip over missing exons. Cells can then produce a truncated form of the dystrophin protein with improved function.
This truncated form of dystrophin is similar to the form that occurs naturally in the milder Becker muscular dystrophy (BMD). For patients with DMD, exon-skipping therapies can slow disease progression, potentially improving quality of life and life expectancy.
Children’s Health was involved in several clinical trials that led to FDA approval of exon-skipping DMD therapies that are currently available.
“Each of these therapies targets specific changes in the DMD gene, so only patients with those specific genetic variants can benefit from this approach,” says Dr. Batley. “Those who are eligible receive these IV medications weekly, either here or at home. Our goal is to participate in new trials with additional exon-skipping medications that target different mutations so more patients can benefit from this treatment.”
Gene replacement therapy with the potential to slow or stop disease progression
In contrast to exon-skipping therapies, gene replacement therapies are designed to replace the entire defective DMD gene. Therapies currently under investigation use viral vectors to deliver microdystrophin, a shortened but functional version of the DMD gene, to muscle cells.
Children’s Health is currently participating in one clinical trial, EMBARK, whose therapy (SRP-9001, or delandistrogene moxeparvovec-rokl/ELEVIDYS) was approved by the FDA in June 2023 for ambulatory patients ages 4 through 5. Later in 2023, Dr. Batley expects to begin two additional trials that will expand eligibility to older patients in later stages of the disease who may no longer be able to walk. The ENVISION trial will investigate SRP-9001 in patients up to age 18, including those who are nonambulatory, and the AFFINITY trial will investigate another therapy, RGX-202, in ambulatory patients up to age 11.
“Many trials are designed for younger, ambulatory patients, before significant progression, because we don’t yet have a way to reverse muscle damage once it has happened,” says Dr. Batley. “The upcoming trials will give us the opportunity to see the potential benefits of these investigational drugs in patients in later stages of the disease.”
If successful, these gene replacement therapies have the potential to slow or stop disease progression, improving quality of life. Because these therapies benefit both skeletal and cardiac muscles, they may help extend life expectancy by delaying or reducing heart and respiratory failure.
Steroid alternatives that retain anti-inflammatory benefits while minimizing side effects
Patients who have DMD often receive corticosteroids, such as prednisone or deflazacort, to reduce inflammation and strengthen muscles. However, long-term use of corticosteroids has significant side effects such as behavior issues, irritability, obesity, decreased bone density, short stature and insulin resistance.
Researchers at Children’s Health and UTSW are participating in a clinical trial of a dissociative steroidal anti-inflammatory investigational drug called vamorolone. This medication shows promise in retaining the anti-inflammatory and muscle-strengthening benefits of corticosteroids while reducing their side effects.
Vamorolone is a liquid medication that patients take orally daily at home. “We’re expecting vamorolone to be submitted to the FDA later this year as another potential treatment option. If it’s approved, we look forward to providing this option to our patients,” Dr. Batley says.
Cardiac-derived cell therapy that encourages muscle cell regeneration
Another proposed treatment aims to address the continuous inflammation, impaired muscle regeneration and progressive fibrosis associated with DMD. Called CAP-1002, this therapy uses human allogeneic cardiosphere-derived cells, manufactured from donor heart tissue. CAP-1002 is thought to modulate immune system activity to decrease inflammation and promote muscle cell regeneration.
Earlier findings in the clinical trial process have shown that CAP-1002 can slow the loss of – and even improve – muscle function in the arms, hands and heart compared to a placebo. CAP-1002 provides a therapeutic approach for any patient with DMD, regardless of their specific genetic mutation.
“This is an exciting potential treatment that may be able to improve both cardiac and skeletal muscle,” says Dr. Batley. “Our trial site is now open for enrollment for patients aged 10 and older. We’re excited to be able to provide a treatment option for older patients with more progressive disease, because many investigational therapies are geared toward younger patients before the onset of significant muscle degeneration.”
Innovative research that supports nationally recognized DMD care
For its commitment to the highest standards of care and excellence in research, the DMD program at Children’s Health is designated as an MDA Care Center by the Muscular Dystrophy Association and as a Certified Duchenne Care Center by Parent Project Muscular Dystrophy. The team of research and clinical physicians collaborates to provide comprehensive care in Children's Health multidisciplinary DMD clinic.
Providers across North Texas and beyond send their patients to Children’s Health DMD center of excellence for exceptional care and investigational therapies that are not widely available.
“We’re dedicated to advancing DMD research, and we won’t stop until there are treatments that change the trajectory of this devastating disease,” Dr. Batley says. “We’re always available to talk to providers who have a patient with DMD – whether they need ongoing management or are looking for a trial to participate in, we partner with providers to get the best possible care for their patients.”
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