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<p>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 (h<i>DMD</i>del45;<i>mdx</i>), 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.</p>

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DG9 boosts PMO nuclear uptake and exon skipping to restore dystrophic muscle and cardiac function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月14日

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  • Md Nur Ahad Shah,
  • Harry Wilton-Clark,
  • Farhia Haque,
  • Brooklynn Powell,
  • Laura Edellein Sutanto,
  • Radha Maradiya,
  • Pavel Zhabyeyev,
  • Rohini Roy Roshmi,
  • Saeed Anwar,
  • Tejal Aslesh,
  • Kenji Rowel Q. Lim,
  • Rika Maruyama,
  • Anne Bigot,
  • Courtney S. Young,
  • Scott Bittner,
  • Melissa J. Spencer,
  • Hong M. Moulton,
  • Gavin Y. Oudit,
  • Toshifumi Yokota

摘要

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.