The use of nucleic acid-based drugs has long been understood as having great promise because of its compelling logic. Many therapeutic companies specializing in this novel form of therapy were established over time. However, the practical development of the drugs, which at first appeared simple, dragged on for decades. It was only in recent years that the first drugs based on oligonucleotides were approved. Nucleic acid technology received a further boost with the development of mRNA-based vaccines in connection with the COVID-19 pandemic.
The challenges that emerged in the use of nucleic acids as drugs were how to enhance binding to the target sequence and thereby increase potency. Also, nucleic acids are rapidly degraded in vivo and therefore an increased lifespan is necessary. As a side effect of treatment, inflammatory effects need to be reduced and at the same time, the pharmacological response needs to be optimized. Finally, delivery needs to be improved depending on the way of drug administration. Many of those challenges could be resolved by chemically modifying the nucleic acids used. On the one hand, there are modifications to the backbone and, on the other hand, modifications at the 2' carbon of the sugar.
Backbone Modifications
Figure: Common backbone modifications utilized in nucleic acid-based drugs. DNA: R=H, RNA: R=OH.
2‘ Modifications
Figure: Common 2’ modifications utilized in nucleic acid-based drugs.
A byproduct of the advances in nucleic acid modifications for drug development is the ability to use these modifications as targets. Tools that can specifically detect a modification can be used to localize a drug in vivo or to monitor its half-life. Rockland currently offers an antibody panel targeted against the PS moiety, which is the most widely used backbone modification.