Oct. 16 (UPI) — Researchers at Children’s National Health System found chronic inflammation is vital for sustained delivery of drug treatment for Duchenne muscular dystrophy.
Since the drug eteplirson disappears from the blood within hours of being taken, the researchers conducted a study focused on finding a way to deliver the drug to muscle and increase its cellular uptake and effectiveness, outlining possible methods for increasing efficacy in a study published Monday in the journal Nature Communications.
Duchenne muscular dystrophy, or DMD, is caused by mutations in the X-linked DMD gene leading to significant muscle degeneration, regeneration, inflammation and fibrosis, which leads to progressive muscle weakness and loss.
DMD is the most common and severe form of muscular dystrophy affecting 1 in 5,000 boys worldwide. Mutations in the DMD gene cause a lack of functional dystrophin, a protein needed to maintain structural support in healthy muscle.
Most boys with DMD are unable to walk in their teens and life expectancy typically does not extend past the early 30s.
The U.S. Food and Drug Administration approved the first exon-skipping medicine for DMD in 2016 to restore dystrophin protein expression in muscle. The drug, eteplirsen, is an antisense phosphorodiamidate morpholino oligomer, or PMO, has shown variable and sporadic results in clinical trials.
For the new study, researchers used an experimental model of DMD that carries a version of the faulty DMD gene known to destroy dystrophin expression. The team labeled the PMO with a fluorescent tag to track the route it takes into muscle fibers.
The experiment revealed the medicine travels to the muscle but only localizes in patches of regenerating muscle where it then accumulates within the infiltrating macrophages, the immune cells involved in inflammatory response.
Even though PMO is cleared from the blood rapidly, the drug remained in the macrophages for up to one week and then entered muscle stem cells. This allowed for direct transportation into regenerating muscle fibers.
“These macrophages appear to extend the period of availability of this medication to the satellite cells and muscle fibers at these sites,” Dr. Terence Partridge, principal investigator in Children’s Center for Genetic Medicine Research, said in a press release.
“Since the macrophages are acting as long-term storage reservoirs for prolonged delivery to muscle fibers, they could possibly represent new therapeutic targets for improving the uptake and delivery of this medicine to muscle.”