Antisense oligonucleotide-based therapies for diseases caused by pre-mRNA processing defects.

Before a messenger RNA (mRNA) is translated into a protein in the cytoplasm, its pre-mRNA precursor is extensively processed through capping, splicing and polyadenylation in the nucleus. Defects in the processing of pre-mRNAs due to mutations in RNA sequences often cause disease. Traditional small molecules or protein-based therapeutics are not well suited for correcting processing defects by targeting RNA. However, antisense oligonucleotides (ASOs) designed to bind RNA by Watson-Crick base pairing can target most RNA transcripts and have emerged as the ideal therapeutic agents for diseases that are caused by pre-mRNA processing defects. Here we review the diverse ASO-based mechanisms that can be exploited to modulate the expression of RNA. We also discuss how advancements in medicinal chemistry and a deeper understanding of the pharmacokinetic and toxicological properties of ASOs have enabled their use as therapeutic agents. We end by describing how ASOs have been used successfully to treat various pre-mRNA processing diseases in animal models.