Duchenne Muscular Dystrophy (DMD) is a progressive disease that strikes young boys. It is universally fatal, but advances in the understanding of its genetic and molecular underpinnings offer hope that gene therapies might one day help, said a researcher at the AMCP Managed Care & Specialty Pharmacy Annual Meeting, in Denver, during the March 29 session, “Duchenne Muscular Dystrophy: Advances and Controversies.”
Just last year, the FDA approved Exondys 51 (eteplirsen) for DMD, over the recommendations of FDA scientists and an external scientific advisory committee. Eteplirsen does an end-run around the gene mutation that causes DMD, bypassing a stop codon in the gene to allow production of a less-flawed version of the dystrophin protein. It only helps 10% to 15% of patients, but clinical testing was, controversially, limited to 12 patients.
The hope is that other gene therapies might one day offer dramatic relief. Until then, incremental clinical advances will continue to improve some patients’ lives.
“There have been dramatic changes in its natural history based largely on multidisciplinary care,” said Dennis J. Matthews, MD, of the University of Colorado School of Medicine in Aurora, Colorado. “What’s really changed over the past 15 or 20 years is the institution of steroids. Steroids have significantly increased the life expectancy and delayed the loss of ambulation.”
“The other areas that have changed significantly are cardiac, pulmonary and nutritional support,” Matthews said. Cardiac nerve conduction defects and cardiomyopathy are common; angiotensin-converting enzyme (ACT) inhibitor therapy or angiotensin receptor-blocking therapy are frequently prescribed.
With the institution of “really good cardiac management,” these advances have changed the natural history of DMD. But it remains a devastating, invariably fatal disease.
Because it is caused by gene mutations on the X chromosome, girls and women can be carriers but patients are boys. The DMD gene mutations disrupt normal production of dystrophin, a structural muscle protein that enhances muscle fiber stability.
Symptoms are usually apparent by age 5 years and include developmental delays in speech and walking, abnormal gait, frequent falling, and difficulty climbing stairs.
“The classic case is a little boy between 3 and 5 years old with a delay in walking and an abnormal gait pattern, with a wide walking base and a very significant enlargement of calf muscles,” Matthews said. “These boys usually have a speech delay, and if you ask them to get up off the ground, you’ll see that they have an abnormal way of doing that.”
Diagnosis was long made on the basis of muscle biopsy but now involves a simple blood draw and X-chromosome gene mutation test. Seventy percent of boys with DMD have a deletion mutation and the other 30% instead have duplication, translocation, or premature stop-codon gene mutations.
“We’re becoming very good at identifying the gene defects, leading to lots of opportunities to develop a lot of treatment modalities,” he noted.