Blitek Mathilde, Phongsavanh Xaysongkhame, Goyenvalle Aurélie
UVSQ, Inserm, END-ICAP, Université Paris-Saclay 78000 Versailles France
LIA BAHN, CSM-UVSQ Monaco Principality of Monaco.
RSC Med Chem. 2024 Jul 19;15(9):3017-3025. doi: 10.1039/d4md00394b. eCollection 2024 Sep 19.
The development of antisense oligonucleotide (ASO)-based therapeutics has made tremendous progress over the past few years, in particular for the treatment of neuromuscular disorders such as Duchenne muscular dystrophy and spinal muscular atrophy. Several ASO drugs have now reached market approval for these diseases and many more are currently under clinical evaluation. Among them, ASOs made of the tricyclo-DNA originally developed by Christian Leumann have shown particularly interesting properties and demonstrated promise for the treatment of Duchenne muscular dystrophy. In this review, we examine the bench to bedside journey of tricyclo-DNA-ASOs from their early preclinical evaluation as fully phosphorotiated-ASOs to the latest generation of lipid-conjugated-ASOs. Finally we discuss the remaining challenges of ASO-mediated exon-skipping therapy for DMD and future perspectives for this promising chemistry of ASOs.
在过去几年中，基于反义寡核苷酸（ASO）的疗法取得了巨大进展，特别是在治疗诸如杜氏肌营养不良症和脊髓性肌萎缩症等神经肌肉疾病方面。目前已有数种ASO药物获批用于治疗这些疾病，还有更多药物正在进行临床评估。其中，由克里斯蒂安·勒曼最初研发的三环DNA制成的ASO展现出了特别有趣的特性，并在杜氏肌营养不良症的治疗中显示出前景。在这篇综述中，我们考察了三环DNA-ASO从早期作为完全磷酸化ASO进行临床前评估到最新一代脂质共轭ASO的从实验室到临床的历程。最后，我们讨论了ASO介导的外显子跳跃疗法在治疗杜氏肌营养不良症方面仍然存在的挑战以及这种有前景的ASO化学的未来前景。
