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.