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.

DNA insecticide developed from the Lymantria dispar 5.8S ribosomal RNA gene provides a novel biotechnology for plant protection

“…Finally, they confirmed the viability of this high-throughput dsRNA delivery method. Currently, research into using this application is not widespread, so the number of publications in the literature concerning the use of contact RNA preparations is limited 12 . The large relative length of the dsRNA fragments used has continued to provide obstacles to further research.…”

“…In a complex natural habitat, such as a forest, the presence of many stress factors (baculoviruses and bacterial infections, UV radiation, air pollution, etc.) may activate an apoptosis–anti-apoptosis system 10,12 . This provides compelling evidence explaining why earlier-stage larvae collected from forests experienced significant mortality as the result of the down-regulation of the target host IAP gene, unlike LdMNPV-free larvae grown under laboratory conditions.…”

Advances in the Understanding of Skin Cancer: Ultraviolet Radiation, Mutations, and Antisense Oligonucleotides as Anticancer Drugs

“…Current use of antisense oligonucleotides in therapeutic medicine may seem exotic, as they were originally developed for and are being used to treat quite rare diseases, such as familial hypercholesterolemia [140], spinal muscular atrophy [141], and Duchenne muscular dystrophy [142]. As we examine how they might help address two difficult cancers, melanoma and Merkel cell carcinoma, it is worth mentioning these drugs and their developers, because they too “chose to address difficult conditions, with seemingly unreachable goals, where conventional approaches had not noticeably succeeded” [143].…”

“…As a result, scientists have included many chemical modifications (phosphorothioates, 2’-O-methyl oligonucleotides, locked nucleic acids, morpholino oligomers, etc.) in the ensuing generations of ASOs to improve binding properties and the ability of ASOs to penetrate cells, to increase their stability in vivo and their efficacy, and to diminish unintended nontarget effects [143]. Fomivirsen, the first antisense drug made with a phosphorothioate backbone, was approved in 1998 by the U.S. Food and Drug Administration (U.S. FDA) and in 1999 by the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of retinitis cytomegalovirus (CMV) in patients with AIDS.…”

“…Several drugs (Kynamro ® , Spinraza ® , EXONDYS 51 TM , etc. ), generally administered via intravenous infusion, are approved today by the FDA [143]. Unfortunately, oligonucleotide-based therapeutics has not yet delivered a clinical drug to the market in the cancer field [146].…”