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Antisense Oligonucleotides for Vaccine Improvement
Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines.
1.1. Earlier Uses of Oligonucleotides in Vaccines
1.2. Birth of ASOs
|Chemical Modifications||Characteristics||Mechanisms||Clinical Use||Limitations|
|Phosphorothioate (PTO), Methylphosphonate
|Either a sulfur atom (PTO), or a methyl group (MPO) substitutes the non-bridging oxygen atoms in the phosphodiester bond.||First generation ASOs promote degradation of target mRNA by RNase H enzyme. They also confer higher solubility, resistance to nuclease degradation, antisense activity and longer plasma half-life as compared with phosphodiester oligonucleotides.||PTO is the most widely used modification of ASOs. Fomivirsen, is a PTO-modified ASO, used as local treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) .||High affinity for various cellular proteins and components of the innate immune system, such as Toll-like receptors (TLRs), with proinflammatory effects.
Commonly reported side effects
following systemic administration of PTO ASOs include fever, activated partial thromboplastin time prolongation, thrombocytopenia,
|ASOs with 2’-O-alkyl modifications of the ribose.
Chimeric ‘gapmer’ ASOs
|2’-O-Methyl (2’-OMe) and 2’-O-Methoxyethyl (2’-MOE) are the most widely studied.
Chimeric ‘gapmer’ ASOs consist in a central ‘gap’ region containing 10 DNA or PTO DNA monomers, flanked on both 5’ and 3’extremities by alkyl modified nucleotides such as 2′-OM or 2’-MOE.
|The PTO DNA induces RNase H cleavage while 2′-OME or 2′-MOE on both sides (5′- and 3′-directions) confers nuclease-resistance, and they can exert activity by a steric interference of translation process.
They are safer than PTO-modified ASOs and exhibit enhanced affinity towards the complementary RNA with better tissue uptake and longer in vivo half-life.
|Mipomersen is used as an adjunct therapy for homozygous familial hypercholesterolemia .
Nusinersen was approved for spinal muscular atrophy treatment .
Apatorsen is a HSP27 targeting ASO that is being studied in phase II clinical trials in patients with metastatic castration resistant prostate cancer  and Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer .
|A subset of 2´-MOE-modified ASOs induced pro-inflammatory cytokines and type I interferons (IFN-α/β) and interaction with innate immune receptors such as TLR9, melanoma-differentiation associated-5 (MDA-5) and IFN-β promoter stimulator-1 (IPS-1).|
|Peptide nucleic acid (PNA)||PNA is a synthetic DNA in which the deoxyribose phosphate backbone is replaced by polyamide linkages.||PNA block the protein expression, by steric hindrance, forming sequence-specific duplex with the targeted mRNA. They are biologically stable and have good hybridization properties.||The potential of PNA as drugs in gene therapy has been hampered by the poor intrinsic uptake of PNA by living cells. Current strategies for improving PNA delivery into the cytosolic space and nucleus include microinjection, electroporation, co-transfection with DNA, or conjugation to lipophilic moieties, nanoparticles, cell-penetrating peptides (CPPs), oligo-aspartic acid, or nuclear localization signal (NLS) peptides to enhance cellular internalization||PNA do not activate the RNase H to cleave the target hybridized RNA. PNA have low solubility and cellular uptake.|
|Phosphoramidate morpholino oligomer (PMO)||PMOs are neutral ASOs. The pentose sugar is substituted by a morpholino ring and the inter-nucleotide linkages are phosphoramidate bonds in place of phosphodiester bonds.||The mechanism of PMO is the translational arrest mediated by steric interference of ribosomal assembly. PMO show fewer nonspecific properties and lesser toxicity than PTO.||Eteplirsen was approved for Duchenne muscular dystrophy (DMD) treatment . Other potential applications include the treatment of viral infections, antibiotic-resistant bacterial infections, and cancers .||PMOs exhibit reduced cellular uptake. Conjugation with peptides such as arginine-rich peptide (ARP) can enhance its cellular uptake and antisense efficacy.|
|Locked nucleic acid (LNA)||LNAs are chemically modified nucleotides with a ribose containing a methylene bridge between the 2′-oxygen and the 4′-carbon of the ribose.||LNA modifications improve the affinity of ASO hybridization towards mRNA target, by increase of the DNA/RNA heteroduplexes thermal stability. LNAs avoid nuclease degradation.||Diverse LNAs are currently in clinical trials by several biotechnology firms.||LNA does not activate RNase. LNA nucleotides can be incorporated at the ends of RNA and DNA sequences to form chimeric oligonucleotides resulting in restoration of RNase H-mediated cleavage of mRNA.|
2. ASOs in Vaccines
2.1. Antigen Modification
2.2. Targeting Host Immune Mechanisms
3. ASOs as Vaccine Adjuvants in Subunit Vaccines
4. Challenges and Opportunities for ASOs Application in Vaccinology
Discovery of new suitable genes to improve vaccine protective immunogenicity against specific infectious or tumoral disease using ASOs.
Development of bioinformatic tools and in vitro systems for ASOs screening to vaccine application.
Discovery of delivery systems that can promote effective ASOs cellular uptake in the immune system.
Studies of stability and antigen-ASOs compatibility in vaccine formulations.
Immunotoxicity studies to discover potential consequences of immune overstimulation.
Studies of efficacy/safety in different genetic contexts.
5. Concluding Remarks
This entry is adapted from 10.3390/biom10020316
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