Expansion of Splice-Switching Therapy with Antisense Oligonucleotides

Since 2016, splice-switching therapy, in which splicing is controlled by antisense oligonucleotides, has been applied in clinical practice for spinal muscular atrophy and Duchenne muscular dystrophy. In the former disease, this therapy induces exon inclusion, while, in the latter, it induces exon skipping, leading expression of functional proteins. Basic and clinical studies of splice-switching therapy for many monogenic diseases have now been conducted. The molecular mechanisms of splice-switching therapy include not only the induction of exon inclusion and skipping, but also the induction of pseudoexon skipping and suppression of splicing sites generated by mutations. In addition, therapies that alter protein function by regulating splicing are being investigated not only for monogenic diseases but also for non-monogenic ones such as cancer and immune-related disorders. It is expected that many of these basic studies will be translated into clinical applications. This review describes the current status of basic research and clinical applications of splice-switching therapy to promote the development of treatments for noncurable diseases.