Macrophages, a type of white blood cell involved in inflammation, readily take up a newly approved medication for Duchenne muscular dystrophy (DMD) and promote its sustained delivery to regenerating muscle fibers long after the drug has disappeared from circulation, an experimental model study led by Children’s National Health System researchers finds. The study, published online Oct. 16, 2017 in Nature Communications, details the cellular mechanisms of morpholino antisense drug delivery to muscles, improving understanding of how these medicines target muscle tissue and suggesting an avenue to improve treatments for DMD, a devastating disease that currently has no cure.
Duchenne is the most common and severe form of muscular dystrophy and affects about 1 in 5,000 boys worldwide. The disease is caused by mutations in the X-linked DMD gene. DMD is characterized by significant muscle degeneration, regeneration, heightened inflammation and fibrosis, leading to progressive muscle weakness and loss, explains study co-leader James S. Novak, Ph.D., a principal investigator in Children’s Center for Genetic Medicine Research. Mutations in the DMD gene lead to a lack of functional dystrophin, a protein critical to maintaining structural support in healthy muscle. Most boys with DMD lose the ability to walk by their teens; life expectancy for people with this disease rarely extends past the early 30s.
Until recently, the only pharmaceutical therapies for DMD targeted the symptoms, rather than its root genetic cause. However, in September 2016 the Food and Drug Administration approved the first exon-skipping medicine for DMD to restore dystrophin protein expression in muscle. Eteplirsen, an antisense phosphorodiamidate morpholino oligomer, has shown significant promise in preclinical studies, but clinical trial results have shown variable and sporadic dystrophin production in the muscles of people who receive it.