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.
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| http://dx.doi.org/10.1039/d4md00394b | DOI Listing |
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