DG9 boosts PMO nuclear uptake and exon skipping to restore dystrophic muscle and cardiac function
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.
Authors
- Kenji Rowel Q. Lim (ORCID: https://orcid.org/0000-0002-5484-4183)
- Harry Wilton-Clark (ORCID: https://orcid.org/0000-0002-2696-265X)
- Gavin Y. Oudit (ORCID: https://orcid.org/0000-0002-9154-9028)
- Anne Bigot (ORCID: https://orcid.org/0000-0003-0337-5425)
- Melissa J. Spencer (ORCID: https://orcid.org/0000-0001-7104-544X)
- Farhia Haque (ORCID: https://orcid.org/0000-0002-6992-7299)
- Pavel Zhabyeyev (ORCID: https://orcid.org/0000-0003-0652-3235)
- Md Nur Ahad Shah (ORCID: https://orcid.org/0000-0001-6548-1501)
- Rohini Roy Roshmi (ORCID: https://orcid.org/0000-0001-6415-6862)
- Saeed Anwar (ORCID: https://orcid.org/0000-0003-3688-5923)
- Courtney S. Young (ORCID: https://orcid.org/0000-0001-9778-876X)
- Scott Bittner
- Tejal Aslesh (ORCID: https://orcid.org/0000-0003-1759-6915)
- Rika Maruyama (ORCID: https://orcid.org/0000-0002-5656-6930)
- Hong M. Moulton (ORCID: https://orcid.org/0000-0002-8095-1513)
- Toshifumi Yokota (ORCID: https://orcid.org/0000-0001-7316-3546)
- Barry C. Powell
- Laura Edellein Sutanto
- Radha Maradiya
Institutions
- Oregon State University (US)
- University of Alberta (CA)
- Inserm (FR)
- University of California, Los Angeles (US)
- Washington University in St. Louis (US)
- Muscular Dystrophy Canada (CA)
- Sorbonne Université (FR)
- Institut de Myologie (FR)
- Centre de Recherche en Myologie
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s41467-025-59494-8
- Citations
- 6
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Heart and Stroke Foundation of Canada
- Children's Health Research Institute
- Women and Children's Health Research Institute
- Muscular Dystrophy Canada
- Alberta Innovates
- Canadian Institutes of Health Research