Evaluation of Chemically Modified Nucleic Acid Analogues for Splice Switching Application.

Abstract

In recent years, several splice switching antisense oligonucleotide (ASO)-based therapeutics have gained significant interest, and several candidates received approval for clinical use for treating rare diseases, in particular, Duchenne muscular dystrophy and spinal muscular atrophy. These ASOs are fully modified; in other words, they are composed of chemically modified nucleic acid analogues instead of natural RNA oligomers. This has significantly improved drug-like properties of these ASOs in terms of efficacy, stability, pharmacokinetics, and safety. Although chemical modifications of oligonucleotides have been discussed previously for numerous applications including nucleic acid aptamers, small interfering RNA, DNAzyme, and ASO, to the best of our knowledge, none of them have solely focused on the analogues that have been utilized for splice switching applications. To this end, we present here a comprehensive review of different modified nucleic acid analogues that have been explored for developing splice switching ASOs. In addition to the antisense chemistry, we also endeavor to provide a brief historical overview of the approved spice switching ASO drugs, including a list of drugs that have entered human clinical trials. We hope this work will inspire further investigations into expanding the potential of novel nucleic acid analogues for constructing splice switching ASOs.