Chapter 17 - Antisense oligonucleotide drugs for neurological and neuromuscular disease

Abstract

Advances in human genetics and neurosciences have elucidated the fundamental mechanisms underlying many inherited neurological diseases and are providing detailed molecular insights into the causes of sporadic neurological diseases, yet disease-modifying therapies are currently unavailable for most of these conditions. There is a need for alternative therapeutic modalities for the treatment of neurological diseases to capitalize on these exciting genetic and genomic findings. One such platform technology is antisense oligonucleotides (ASOs). ASOs are synthetic nucleic acids or nucleic acid analogs, generally 13–25 nucleotides in length, which bind to RNA by Watson–Crick base paring. Upon binding the ASO modulates the function of the RNA, either promoting its degradation or altering its function to disrupt the flow of genetic information from DNA to proteins. In addition to protein-coding RNAs, noncoding RNAs can be targets of ASO-based drugs, significantly broadening therapeutic targets for drug discovery compared to small molecules and protein-based therapeutics. Antisense technology provides a direct route from human genomic information to creating drugs that address the fundamental cause of a broad range of neurological and neuromuscular disorders.