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

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 and Toshifumi Yokota ()
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Md Nur Ahad Shah: University of Alberta
Harry Wilton-Clark: University of Alberta
Farhia Haque: University of Alberta
Brooklynn Powell: University of Alberta
Laura Edellein Sutanto: University of Alberta
Radha Maradiya: University of Alberta
Pavel Zhabyeyev: University of Alberta
Rohini Roy Roshmi: University of Alberta
Saeed Anwar: University of Alberta
Tejal Aslesh: University of Alberta
Kenji Rowel Q. Lim: Washington University in St. Louis
Rika Maruyama: University of Alberta
Anne Bigot: Centre de Recherche en Myologie
Courtney S. Young: University of California
Scott Bittner: Oregon State University
Melissa J. Spencer: University of California
Hong M. Moulton: Oregon State University
Gavin Y. Oudit: University of Alberta
Toshifumi Yokota: University of Alberta

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59494-8

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