Targeted gene therapy aimed at the muscles used for breathing improved respiratory muscle health in a mouse model of Duchenne muscular dystrophy (DMD) while reducing the risks tied to high drug exposure, according to a study published recently in Respiratory Physiology and Neurobiology.
Breathing muscles are critical in DMD because gradual weakening often leads to respiratory failure.
Gene therapy that delivers adeno-associated virus vectors carrying microdystrophin to the whole body (the approach used with the gene therapy delandistrogene moxeparvovec-rokl, or Elevidys) helps the muscles retain strength, but carries risks. This study found that delivering these vectors specifically toward the diaphragm and tongue, rather than equally to the whole body, helped these vulnerable muscles while making less impact on the liver than current gene therapy approaches.
The research team used D2.mdx mice, a DMD model that develops early respiratory problems. They compared high body-wide doses of gene therapy — the approach currently used — with two targeted approaches: one that delivered smaller amounts of the gene therapy directly to the tongue and chest, and one that combined delivering smaller amounts to both these muscles and the entire body.
Read more about the prognosis of DMD
All delivery strategies improved dystrophin staining in the diaphragm and tongue. Mice receiving the high system-wide intravenous dose showed the most dystrophin but also the greatest buildup of vector genomes in the liver, a known safety concern.
Muscle tissue from untreated D2.mdx mice showed the classic features of DMD: large numbers of centralized nuclei, signs of inflammation and wide variation in fiber size. All treated groups had far fewer centralized nuclei in both the diaphragm and tongue. The reductions were meaningful and consistent, signaling healthier muscle repair.
Breathing tests also reflected these changes. Young D2.mdx mice had reduced tidal volume and airflow compared with healthy mice, but treated mice showed stronger breathing patterns over time. Combination dosing often aligned respiratory responses more closely with healthy controls at 28 weeks, especially during challenges involving low oxygen and high carbon dioxide.
“These findings suggest that this combinatorial approach may offer an optimal therapeutic window by reducing systemic exposure while enhancing transduction of respiratory targets,” explained this study’s authors.
For people living with DMD, these results reinforce that gene therapy may not need to bathe the entire body at maximal doses to help breathing. A more tailored approach could strengthen essential muscles, reduce future respiratory decline and offer safer long-term care options.
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