Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by DMD gene mutations, leading to the loss of functional dystrophin. While antisense oligonucleotide (ASO)-mediated exon skipping offers therapeutic potential, its efficacy in cardiac muscle remains limited. Here, we investigate DG9, a cell-penetrating peptide derived from human polyhomeotic 1 homolog (Hph-1) transcription factor, as an enhancer of phosphorodiamidate morpholino oligomer (PMO)-based therapy targeting exon 44. In a humanized DMD mouse model (hDMDdel45;mdx), DG9-PMO significantly increases exon skipping, restores dystrophin expression, and improves muscle function, particularly in the heart. Mechanistically, DG9-PMO enhances intracellular uptake through multiple endocytic pathways and achieves superior nuclear localization. Compared to the benchmark R6G peptide, DG9-PMO exhibits greater efficacy in cardiac tissue with no detectable toxicity. These findings highlight DG9-PMO as a promising next-generation exon-skipping therapy with potential clinical relevance for improving both skeletal and cardiac outcomes in DMD patients.
© 2025. The Author(s).