Overview of Alternative Oligonucleotide Chemistries for Exon Skipping

The chemistry of the oligonucleotide backbone is crucial to obtaining high activity in vivo in exon skipping applications. Apart from the ability to bind strongly and sequence-specifically to pre-mRNA targets, the type of backbone also influences cell delivery, in vivo pharmacology, bio-distribution, toxicology, and ultimately the therapeutic use in humans. Reviewed here are classes of oligonucleotide commonly used for exon skipping applications, namely negatively charged backbones typified by RNA analogues having 2′-O-substitution and a phosphorothioate linkage and charge-neutral backbones such as PNA and PMO. Also discussed are peptide conjugates of PNA and PMO that enhance cellular and in vivo delivery and their potential for drug development. Finally, the prospects for development of other analogue types in exon skipping applications are outlined.