Regulation of pre-mRNA splicing by antisense oligonucleotides.

Numerous human diseases arise from mutations that result in aberrant RNA splicing. To date, traditional therapeutic approaches have not been successful in targeting these mutations and restoring correct splicing. Antisense oligonucleotides may provide a novel and effective way to restore correct splicing in mutant genes. Historically, antisense oligonucleotides have been used to decrease mRNA transcripts of disease gene products through an RNase H-dependent mechanism. Through chemical modifications of antisense oligonucleotides, it has been possible to generate compounds that bind to specific mRNA sequences with high affinity, yet do not cause the degradation of the RNA transcript. By directing chemically-modified oligonucleotides to regions of the pre-mRNA important for splicing, it may be possible to inhibit splicing at mutant splice sites. This novel and relatively unexplored application of antisense technology could be of tremendous therapeutic benefit in the treatment of human disease.