Antisense oligonucleotides (ASOs) are a new class of drugs that, through precise targeting, could correct genetic defects for rare inherited diseases, modulate autoimmune or neurodegenerative diseases or target tumours or viruses. They are short strands of DNA or RNA that can bind to RNA.
They usually act through binding (hybridisation, binding through Watson–Crick base pairing) to specific (target) sequences in coding RNA (pre‐mRNA or mRNA), so they are highly accurate. They can modulate the function of the target RNA. They can be manufactured at a large scale in a standardised manner. What more they do not need to be incorporated into genomic DNA with the use of viral vector as in case of other genetic therapies.
There are different types of AONs, defined by their chemical structure, i.e. 20 O-methyl phosphorothioate oligonucleotides (2OMe), locked nucleic acids (LNAs), phosphorodiamidate morpholino oligomers (PMO) and peptide nucleic acids (PNAs). They can be bound with other compounds (moieties) to increase their delivery, such as cell-penetrating peptides (CPPs).
AON therapy development is a dynamic and active field. To date, four AON compounds have received a marketing authorisation and more than 100 clinical trials with antisense compounds. The main hurdle for their efficacy seems to be their deficient delivery to target tissues but, while translational research on ASO is surging, very little is known about the mechanisms by which ASOs are taken up by different tissues and specific cell. It is assumed that on average < 1% of AONs reach the correct cellular compartment. Furthermore, due to the body's tissue barriers, the circulation of AONs is restricted, for example, most AONs are not able to reach the central nervous system (CNS) after injection (systemic delivery).