Systemic Delivery of Skeletal-Muscle-Targeted DMD mRNA Using Engineered Extracellular Vesicles

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder caused by mutations in the DMD gene, which encodes dystrophin. Although gene therapy using viral vectors has shown promise for the treatment of DMD, the clinical application of viral gene therapies is limited by vector toxicity, immunogenicity and the inability to package full-length dystrophin. Recent advances in messenger RNA (mRNA) technology offer a non-integrating, transient approach to restoring protein expression.

Here the authors report the systemic delivery of skeletal-muscle-targeted full-length DMD mRNA in a murine model of DMD using allogenically engineered targeting extracellular vesicles (DMD t-EVs). This approach restores the endogenous translation of wild-type dystrophin and substantially improves muscle function. We further demonstrate the safety and biocompatibility of DMD t-EVs in non-human primates, supporting their translational potential.

These findings highlight the promise of mRNA-loaded extracellular vesicles as a therapeutic platform for treating genetic disorders involving large, difficult-to-package genes. The study demonstrates that engineered extracellular vesicles can effectively deliver full-length mRNA to skeletal muscle without the limitations associated with viral vectors. This represents a significant advancement in the field of gene delivery systems.

The authors note that while these findings are promising, further research is needed to establish safety and efficacy in human clinical trials. The use of allogenically engineered extracellular vesicles introduces considerations regarding immunogenicity and long-term stability that require careful evaluation. These results should be interpreted within the context of preclinical research.

This work underscores the potential of non-viral delivery systems for treating genetic disorders. The ability to deliver full-length mRNA without viral vectors addresses critical limitations in current gene therapy approaches. Continued investigation into extracellular vesicle-based platforms may lead to effective therapeutic strategies for DMD and other genetic conditions.