Preclinical Development – Biomolecular
2019 PharmSci 360
Antisense oligonucleotides (AONs) are chemically modified single stranded DNA molecules, typically 14- to 20 nucleotides in length, developed for therapeutic use. To date, five AONs have been approved for treatment, and there are currently more than 30 AONs in active clinical development around the world. AONs are designed to bind to an RNA target of interest and modulate its function. AON mechanisms of action include eliciting ribonuclease H-mediated cleavage of the RNA, interfering with splicing during processing of the RNA from primary to mature transcript, sequestering of small non-coding microRNAs, and modulation of protein translation rates by blocking regulatory sequence elements in the mRNA. Developments in AON mechanisms of action go hand-in-hand with research on how to disrupt normal RNA function, or correct RNA dysfunction, to modulate disease progression. That is, exploring how an RNA of interest is causatively linked to disease, as well as how to engineer AONs with a mechanism of action able to affect this target-to-disease link, are activities that are often considered in parallel when evaluating new RNA targets for AON drug discovery. This presentation will give current status in the field with examples from our own work, and outline possible future developments.