Antisense Oligonucleotides: problems with use and solutions
Pierre-Olivier Fiset and Abdelilah Soussi Gounni
Abstract
Antisense oligonucleotides show great potential as a molecular biological tool and therapeutic agent but there are some difficulties while using them such as toxicity, non-specific side effects, and low intracellular uptake. In human clinical trials, phosphorothioate oligonucleotides (PS-ODNs), the first generation antisense oligonucleotides show various hematologic toxicities mainly due to non-specific effects. Due to their charge and polarity, uptake by targeted cell is not efficient. Additionally, the main mechanism of action of first generation antisense oligonucleotides is limited to the induction of ribonuclease digestion of mRNA. To overcome the problems experienced with antisense oligonucleotides, drug delivery vectors can help in the specific delivery of the oligonucleotides, their uptake from the circulation, and the prevention non-specific effects. Second generation antisense oligonucleotides offer other mechanisms of action to inhibit the production of proteins thus having a potential an alternative antisense therapy to PS-ODNs. With these modifications, Antisense oligonucleotides can therefore efficiently disrupt signaling by causing a reversible knockout of receptors or intracellular secondary mediators in assays to explore receptor function or as well as a therapeutic agent.