Shah Md Nur Ahad, Wilton-Clark Harry, Haque Farhia, Powell Brooklynn, Sutanto Laura Edellein, Maradiya Radha, Zhabyeyev Pavel, Roshmi Rohini Roy, Anwar Saeed, Aslesh Tejal, Lim Kenji Rowel Q, Maruyama Rika, Bigot Anne, Young Courtney S, Bittner Scott, Spencer Melissa J, Moulton Hong M, Oudit Gavin Y, Yokota Toshifumi
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2G3, Canada.
Nat Commun. 2025 May 14;16(1):4477. doi: 10.1038/s41467-025-59494-8.
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.
杜氏肌营养不良症（DMD）是一种由DMD基因突变引起的严重神经肌肉疾病，导致功能性抗肌萎缩蛋白缺失。虽然反义寡核苷酸（ASO）介导的外显子跳跃具有治疗潜力，但其在心肌中的疗效仍然有限。在这里，我们研究了DG9，一种源自人类多同源盒蛋白1同源物（Hph-1）转录因子的细胞穿透肽，作为基于磷酰胺吗啉代寡聚物（PMO）靶向外显子44治疗的增强剂。在人源化DMD小鼠模型（hDMDdel45；mdx）中，DG9-PMO显著增加外显子跳跃，恢复抗肌萎缩蛋白表达，并改善肌肉功能，尤其是在心脏中。从机制上讲，DG9-PMO通过多种内吞途径增强细胞内摄取，并实现卓越的核定位。与基准R6G肽相比，DG9-PMO在心脏组织中表现出更高的疗效，且未检测到毒性。这些发现突出了DG9-PMO作为一种有前景的下一代外显子跳跃疗法，对改善DMD患者的骨骼和心脏预后具有潜在的临床意义。
