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Antisense Oligonucleotides: an Emerging Area in Drug Discovery and Development

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Antisense Oligonucleotides: an Emerging Area in Drug Discovery and Development Journal of Clinical Medicine Review Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development Karishma Dhuri 1, Clara Bechtold 1, Elias Quijano 2, Ha Pham 3, Anisha Gupta 4, Ajit Vikram 5 and Raman Bahal 1,* 1 Department of Pharmaceutical Science, University of Connecticut, Storrs, CT 06269, USA; [email protected] (K.D.); [email protected] (C.B.) 2 Department of Genetics, Yale University, New Haven, CT 06520, USA; [email protected] 3 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232-5671, USA; [email protected] 4 Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA; [email protected] 5 Division of Cardiovascular Medicine, Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USA; [email protected] * Correspondence: [email protected] Received: 24 April 2020; Accepted: 24 June 2020; Published: 26 June 2020 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. Keywords: RNA; antisense oligonucleotides; chemical modifications; clinical trials 1. Introduction Aberrant protein production or metabolism is associated with numerous devastating diseases and disorders [1–4]. As proteins are produced by decoding information stored in messenger RNA (mRNA), aberrant protein production can be regulated by targeting mRNA. Additionally, a greater understanding of RNA has unraveled its multifaceted roles. Until the advent of non-coding RNAs (ncRNAs), mRNA was only considered as the mediator between DNA and the ribosome for protein synthesis. Among ncRNAs, microRNA (miRNA) [5], transfer RNA-derived small RNA [6], pseudogenes [7], PIWI-interacting RNA [8], long ncRNAs (lncRNAs) [9], and circular RNAs [10] have been identified as critical regulators of biological functions through modulation of gene expression. Hence, the antisense strategy comprising of targeting pre-mRNA, mRNA, or ncRNAs can alter the production of disease-causing proteins for therapeutic interventions. Unlike small molecule-based protein targeting, antisense drugs exhibit their effect by Watson–Crick base pairing rules with target RNA sequence. This principle of Watson–Crick molecular recognition provides the antisense field more flexibility in J. Clin. Med. 2020, 9, 2004; doi:10.3390/jcm9062004 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2004 2 of 24 RNA-based drug design and expedites its development, which is imperative for targeting a myriad of rare and genetic diseases [11]. The amalgamation of chemical structure modifications of oligonucleotides and diverse delivery platforms provides an additional boost to the antisense field. Recent United States Food and Drug Administration (FDA) approval of several nucleic acid-based drugs has further spurred interest in the antisense research. Presently, numerous antisense drug candidates are in clinical trials to treat cardiovascular, metabolic, endocrine, neurological, neuromuscular, inflammatory, and infectious diseases [12]. This review provides a brief overview of the structural modifications of new generation antisense oligonucleotides (ASOs), their mechanisms of action, delivery strategies, and comprehensive information about FDA-approved antisense therapies and current antisense-based drug candidates in clinical trials. 2. Oligonucleotide Modifications In prior studies, ASOs based on phosphodiester backbone (also known as unmodified ASOs) were J. Clin. Med. 2020, 9, x FOR PEER REVIEW 4 of 24 usedJ. Clin. to Med. target 2020, 9 RNA, x FOR withPEER REVIEW moderate success. However, due to the presence of a phosphodiester3 of 24 bond, unmodified ASOs are susceptible to nuclease degradation [13]. In addition, the large size and charge of J. Clin. Med. 2020, 9, x FORTable PEER 1. ChemicalREVIEW modifications of antisense oligonucleotides (ASO). 3 of 24 Higher binding affinity, no immune unmodifiedJ. Clin. Med. 2020 ASOs, 9, x FOR restrict5′methylcytosine PEER REVIEW their passive diffusion intoRNase the H1 cell cleavage [14]. Hence, newer generation,3 of 24 chemically Name Structure Mechanism Properties stimulation J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 24 modified ASOs haveTable been 1. Chemical explored modificationsPhosphate to increase of modification antisense their oligonucleotides efficacy, enzymatic (ASO). stability, and decrease immune Table 1. Chemical modifications of antisense oligonucleotides (ASO). response andName off -target toxicityStructure (Table 1). Mechanism Properties J. Clin. Med. 2020, 9, x FORTable PEER 1. REVIEWChemical modifications of antisense oligonucleotides (ASO). 3 of 24 Name Structure PhosphateMechanism modification Properties Name Structure Phosphate Mechanismmodification Properties TableTable 1. Chemical 1. Chemical modifications modifications of antisense of oligonucleotides antisense oligonucleotides (ASO). (ASO). Phosphorothioate (PS) PhosphateRNase modification H1 cleavage Enzymatic stability Name Structure Mechanism Properties NameG-clamp Structure MechanismSteric hindrance Higher binding Properties affinity Phosphorothioate (PS) PhosphateRNase modification H1 cleavage Enzymatic stability Phosphate modification Phosphorothioate (PS) RNase H1 cleavage Enzymatic stability Phosphorothioate (PS) Sugar phosphateRNase H1modification cleavage Enzymatic stability Phosphorothioate (PS) RNase H1 cleavage Enzymatic stability Phosphorothioate (PS) Sugar phosphate modificationRNase H1 cleavage Enzymatic stability Phosphorodiamidate2.4. Locked Nucleic Acids (LNAs)Sugar phosphate Steric hindrance/splice modification Improved aqueous solubility, higher morpholino (PMO) Sugar phosphatemodulation modification binding affinity Phosphorodiamidate Steric hindrance/splice Improved aqueous solubility, higher Sugar phosphateSugar phosphatemodificationmodification Phosphorodiamidatemorpholino (PMO) Steric modulationhindrance/splice Improved aqueousbinding affinitysolubility, higher Phosphorodiamidatemorpholino (PMO) Stericmodulation hindrance/splice Improved bindingaqueous affinity solubility, higher morpholino (PMO) modulation binding affinity Phosphorodiamidate Steric hindrance/splice Improved aqueous solubility, higher Phosphorodiamidate Steric hindrance/splice Improved aqueous solubility, higher morpholino (PMO) Steric hindrance/splicemodulation Enzymatic stability, higher bindingbinding affinity Peptidemorpholino nucleic acid(PMO) (PNA) modulation binding affinity modulation affinity, no immune activation Steric hindrance/splice Enzymatic stability, higher binding Peptide nucleic acid (PNA) Steric modulationhindrance/splice Enzymaticaffinity, nostability, immune higher activation binding Peptide nucleic acid (PNA) Sugar modification Stericmodulation hindrance/splice Enzymaticaffinity, nostability, immune higher activation binding PeptidePeptide nucleic nucleic acidacid (PNA) Steric hindrance/splice Enzymatic stability, higher binding affinity, modulation affinity, no immune activation (PNA) Locked nucleic acids contain a constrainedmodulation methylene bridge between 2′ nooxygen immune and activation 4′ carbon SugarSteric modification hindrance/splice Enzymatic stability, higher binding Peptide nucleicof acidthe (PNA)ribose ring and display a strong binding affinity to the target DNA or RNA sequences due to SugarSteric modification modulationhindrance/RNase Higheraffinity, binding no immune affinity, activation enzymatic Locked nucleic acid (LNA) their preorganized structure.Sugar Each modification H1lockedSugar cleavage modificationnucleic acid (LNA) modificationstability increases the melting temperature of the duplex by 2–8°CSteric hindrance/RNase [30]. LNAs ex pressHigher their binding antisense affinity, ability enzymatic by steric hindrance Locked nucleic acid (LNA) Sugar modification mechanism. Diverse, comprehensive Steric H1hindrance/RNase LNA cleavage designs, gapmer,Higher mixmer, bindingstability affinity, and other enzymatic modifications have LockedLocked nucleic nucleic acidacid (LNA) Steric hindrance/RNase H1 been evaluated for their antisenseSteric activity H1hindrance/RNase cleavage and compared Higher with unmodifiedbindingstability Higheraffinity, ASOs. bindingenzymatic Gapmers a ffinity, enzymaticare LNA- stability Locked(LNA) nucleic acid (LNA) cleavage H1 cleavage stability DNA-LNA-based designs that contain continuous DNA nucleotides interspaced between two over Steric hindrance/RNase Higher binding affinity, enzymatic Locked nucleichanged
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