Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development

Abstract

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes. To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity. In this regard, several chemical modifications and diverse delivery strategies have been explored. In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs. Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications. We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies.

Gene regulation by long non-coding RNAs and its biological functions

“…Moreover, fused aptamers may also be used for targeted intracellular delivery of these oligo-based drugs 224 . Several mRNA-targeting ASOs have already been approved by the FDA and the European Medicines Agency 225 or have advanced to clinical trials 225 , and several ASOs targeting oncogenic lncRNAs are under development and protected by patents.…”

Formulation of PLGA nanoparticles containing short cationic peptide nucleic acids

“…miRs are small non-coding RNAs (~22–25 nucleotide length) which negatively regulates the expression of several mRNAs [21] . Dysregulation of miRs has been reported to be associated with pathogenesis of cancer, cardiovascular, muscle as well as neurodegenerative disorders [22 , 23] . These miRs bind to the target mRNAs via a short 8 mer sequence called seed region which is critical for activating the RNA induced silencing complex (RISC) assembly.…”

Cell Penetrating Peptides Used in Delivery of Therapeutic Oligonucleotides Targeting Hepatitis B Virus

“…Interestingly, cholesterol-siRNA conjugates can reach specific tissues and inhibit gene expression [ 59 ]. Other lipid-based-systems have been used for chronic HBV treatment and greatly increase siRNA activity when compared to uncoupled siRNA molecules [ 59 , 60 ].…”

“…Moreover, Polymers used as vehicles protect their cargos against nuclease degradation. In addition, the combination between negatively charged oligonucleotides and cationic Polymers leads to formation of polyplexes which favor cellular uptake of molecule [ 60 ]. Thus, these electrostatic properties allow polymer-based carriers to improve intracellular internalization of oligonucleotides such as siRNA, consequently these polyplexes increase the gene silencing [ 59 ].…”

“…Aptamers are synthetic oligonucleotides of 20 to 80 bases that are able to bind to specific molecules such as siRNA with great affinity. In addition, aptamers are able to recognize cell surface receptors in order to mediate targeted delivery of bioactive molecules both in vitro and in vivo [ 60 ]. Thus, aptamers can to be used as vehicles to delivery antisense molecules such as siRNA and PNA into the cells to control gene expression by their silencing.…”