CHAPTER 6: Splicing Modulation for Therapeutics

For most protein-coding genes, the genetic code is dispersed over a number of exons, which are interspersed by longer non-coding sequences, the introns. Translation of the messenger RNA to protein requires removal of the introns and ligation of the exons, a procedure called precursor mRNA (pre-mRNA) splicing. Soon after the discovery of splicing, it was found that defects in pre-mRNA splicing are a common underlying factor of genetic and acquired diseases. Despite the complexity of splicing, it can be intentionally modulated in different ways. This chapter gives an overview of antisense oligonucleotide-mediated splicing modulation and its progress towards therapeutics. It outlines how this approach can be exploited to restore cryptic splicing, restore open reading frames, establish exon inclusion, alter the ratio of alternatively spliced transcripts and induce the production of less toxic or non-toxic proteins. For each application, specific diseases for which antisense oligonucleotide-mediated splicing modulation has been tested are used to illustrate the approach.