Phongsavanh Micky, Bizot Flavien, Saoudi Amel, Gastaldi Cecile, Le Coz Olivier, Tensorer Thomas, Brisebard Elise, Garcia Luis, Goyenvalle Aurélie
Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.
Medical Biology Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco.
Int J Mol Sci. 2025 Mar 13;26(6):2583. doi: 10.3390/ijms26062583.
Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the progressive degeneration of skeletal and cardiac muscles due to the absence of dystrophin. Exon-skipping therapy is among the most promising approaches for treating DMD, with several antisense oligonucleotides (ASO) already approved by the FDA; however, their limited efficacy highlights substantial potential for further improvement. In this study, we evaluate the potential of combining ASO with valproic acid (VPA) to enhance dystrophin expression and improve functional outcomes in a murine model of DMD. Our results indicate that the ASO+VPA treatment significantly increases dystrophin restoration across various muscle tissues, with particularly pronounced effects observed in cardiac muscle, where levels are nearly doubled compared to ASO monotherapy. Additionally, we demonstrate significant improvements in functional outcomes in treated mice. Our findings suggest that the combined ASO+VPA therapy holds promise as an effective therapeutic approach to ameliorate muscle function in DMD, warranting further exploration of its mechanistic pathways and long-term benefits.
杜氏肌营养不良症（DMD）是一种严重的遗传性疾病，其特征是由于缺乏抗肌萎缩蛋白而导致骨骼肌和心肌进行性退化。外显子跳跃疗法是治疗DMD最有前景的方法之一，已有几种反义寡核苷酸（ASO）获得了美国食品药品监督管理局（FDA）的批准；然而，它们有限的疗效凸显了进一步改善的巨大潜力。在本研究中，我们评估了将ASO与丙戊酸（VPA）联合使用以增强抗肌萎缩蛋白表达并改善DMD小鼠模型功能结果的潜力。我们的结果表明，ASO+VPA治疗显著增加了各种肌肉组织中的抗肌萎缩蛋白恢复，在心肌中观察到的效果尤为明显，与ASO单一疗法相比，其水平几乎翻倍。此外，我们证明了治疗小鼠的功能结果有显著改善。我们的研究结果表明，ASO+VPA联合疗法有望成为改善DMD肌肉功能的有效治疗方法，值得进一步探索其作用机制和长期益处。
