An investigational RNA therapy called RAG-18 showed early evidence of increasing utrophin levels and improving muscle tissue characteristics in boys with Duchenne muscular dystrophy (DMD), offering a potential treatment approach that could work regardless of the genetic mutation causing the disease.
Preliminary results from the first three participants in an ongoing phase 1 trial presented at the 31st Annual Congress of the World Muscle Society (WMS 2026), held in Hiroshima, Japan, also showed an encouraging safety profile, although further research is needed to establish whether these changes translate into lasting clinical benefits.
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DMD is caused by mutations that lead to a lack of dystrophin, a protein that protects muscle fibers from damage. RAG-18 uses small activating RNAs to increase production of utrophin, a naturally occurring protein that can perform some of dystrophin’s functions at the muscle membrane. Because this approach does not depend on a specific DMD mutation, it could potentially benefit a broad range of patients.
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The ongoing first-in-human, open-label, dose-escalation phase 1 trial (NCT07282652) enrolled ambulatory boys aged 4 to 15 years who received intravenous RAG-18 at 15 mg/kg every four weeks for four doses while continuing stable corticosteroid treatment. At day 113, muscle biopsies showed utrophin increases of 3.47-fold to 5.25-fold in normal muscle fibers and 4.08-fold to 4.67-fold in regenerating fibers across the three participants.
“These findings provide the first clinical proof-of-mechanism for [self-amplifying] RNA-mediated protein upregulation in human tissue, delivering coherent molecular, histologic, biomarker, and functional evidence to support the continued advancement of RAG-18 as a universal therapeutic strategy for DMD,” the researchers said.
The biopsies also revealed changes in muscle structure. The proportion of normal muscle fibers increased from 75% to 90%, 80% to 87% and 85% to 90% across the participants. Mean muscle fiber diameter increased by 5.34, 13.03 and 27.50 micrometers, respectively. Intramuscular fat fraction decreased from 15% to 7%, 15% to 5% and 8% to 5%. Maximum reductions in blood creatine kinase, a marker of muscle injury, ranged from 26.8% to 63.9%.
Early functional findings were mixed. Predicted forced vital capacity and forced expiratory volume in one second increased by as much as 16.0% and 17.2%, respectively, while one participant improved his 6-minute walk distance by 45.5 meters.
All three participants saw rebounds in North Star Ambulatory Assessment scores, a common measurement of function in DMD. However, the broader study report described variable walking outcomes, including a decline in distance for one participant, underscoring the uncertainty of early results.
No dose-limiting toxicities, serious adverse events or grade 3 or higher treatment-emergent adverse events occurred among the three boys. No dose reductions or treatment discontinuations were reported.
Cohort 2, which is evaluating a 30 mg dose, is fully enrolled.
For patients and families, RAG-18 represents a potential mutation-independent treatment strategy, but it remains experimental. The small number of participants and limited follow-up prevent conclusions about long-term safety, preservation of walking ability or prevention of respiratory and cardiac complications.
