A Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: We Should Continue the Journey

Abstract

Antisense oligonucleotides (ASO), short single-stranded polymers based on DNA or RNA chemistries and synthesized in vitro, regulate gene expression by binding in a sequence-specific manner to an RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense and nucleic acid nanotechnologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. Today the majority of ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake. This review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the elaboration of unmodified insect-specific DNA insecticides and RNA preparations in the areas of agriculture and forestry, a relatively new branch of ASO that allows circumvention of the use of non-selective chemical insecticides. When considering the variety of successful ASO modifications with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases

“…Novel miRNA therapeutics have been developed in the past few years, but some therapeutic miRNA studies have already been terminated during the preclinical stage because of side effects involving liver damage and poor miRNA stability (133). However, miRNA drug delivery, efficacy, and safety issues are currently being addressed, and recently, the first miRNA-based therapeutic, miravirsen, an inhibitor of miR-122-5p, yielded positive results in a phase II clinical trial (134). Further optimization of miRNA therapeutics may yield a wider spectrum of successful miRNA drugs in the years to come, possibly including inflammasome-modulating miRNAs for the treatment of autoimmune disorders.…”

Opportunities and challenges for the clinical translation of structuredDNAassemblies as gene therapeutic delivery and vaccine vectors

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“…Distribution and accumulation in tissues of interest, PK and PD, are the essential criteria typically used in the pharmaceutical industry for the selection of a drug's indication. Although TNAs are used for a variety of indications, only a handful of these concepts reached the approval stage (Levin, 2017, 2019; Oberemok et al, 2018). The main indication extensively explored for NANPs is cancer (Etheridge et al, 2013), while emerging applications include vaccines and immunotherapies (Chandler & Afonin, 2019).…”

“…DNA molecules with a natural phosphodiester backbone are generally more stable chemically than RNA (Oberemok et al, 2018). This stability can be increased further by a variety of chemical alterations including, but not limited to, phosphodiester and methylphosphonate modifications of phosphate groups, 2′‐fluoro modification of the sugar moiety, and morpholino backbones that stabilize against nucleases (Oberemok et al, 2018).…”

“…DNA molecules with a natural phosphodiester backbone are generally more stable chemically than RNA (Oberemok et al, 2018). This stability can be increased further by a variety of chemical alterations including, but not limited to, phosphodiester and methylphosphonate modifications of phosphate groups, 2′‐fluoro modification of the sugar moiety, and morpholino backbones that stabilize against nucleases (Oberemok et al, 2018). When DNA is organized into complex 3D origami structures, nuclease and ionic stability also depend on the number of duplexes crosslinked per edge (e.g., 2‐ versus 6‐ versus 24‐helix bundles) and the presence of magnesium and sodium ions (Kielar et al, 2018), as noted at the outset of this review.…”