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Nature Reviews. Drug Discovery Oct 2020Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation,... (Review)
Review
Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.
Topics: Drug Approval; Drug Delivery Systems; Gene Expression Regulation; Humans; Oligonucleotides
PubMed: 32782413
DOI: 10.1038/s41573-020-0075-7 -
Nucleic Acid Therapeutics Apr 2023Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional... (Review)
Review
Drug Metabolism and Pharmacokinetics of Antisense Oligonucleotide Therapeutics: Typical Profiles, Evaluation Approaches, and Points to Consider Compared with Small Molecule Drugs.
Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional approaches. Technical advances in chemical modification and drug delivery systems have led to the generation of compounds with excellent profiles as pharmaceuticals, and 16 oligonucleotide therapeutics have been marketed to date. There is a growing need to develop optimal and efficient approaches to evaluate drug metabolism and pharmacokinetics (DMPK) and drug-drug interactions (DDIs) of oligonucleotide therapeutics. The DMPK/DDI profiles of small molecule drugs are highly diverse depending on their structural and physicochemical characteristics, whereas oligonucleotide therapeutics share similar DMPK profiles within each chemistry type. Most importantly, the mechanisms and molecules involved in the distribution and metabolism of oligonucleotides differ from those of small molecules. In addition, there are considerations regarding experimental approaches in the evaluation of oligonucleotides, such as bioanalytical challenges, the use of radiolabeled tracers, materials for metabolism/DDI studies, and methods to study biodistribution. In this review, we attempt to summarize the DMPK characteristics of antisense oligonucleotide (ASO) therapeutics and discuss some of the issues regarding how to optimize the evaluation and prediction of the DMPK and DDI of ASOs.
Topics: Oligonucleotides, Antisense; Pharmaceutical Preparations; Tissue Distribution; Oligonucleotides; Drug Delivery Systems
PubMed: 36735616
DOI: 10.1089/nat.2022.0054 -
Future Medicinal Chemistry 2015Oligonucleotide therapeutics have the potential to become a third pillar of drug development after small molecules and protein therapeutics. However, the three approved... (Review)
Review
Oligonucleotide therapeutics have the potential to become a third pillar of drug development after small molecules and protein therapeutics. However, the three approved oligonucleotide drugs over the past 17 years have not proven to be highly successful in a commercial sense. These trailblazer drugs have nonetheless laid the foundations for entire classes of drug candidates to follow. This review will examine further advances in chemistry that are earlier in the pipeline of oligonucleotide drug candidates. Finally, we consider the possible effect of delivery systems that may provide extra footholds to improve the potency and specificity of oligonucleotide drugs. Our overview focuses on strategies to imbue antisense oligonucleotides with more drug-like properties and their applicability to other nucleic acid therapeutics.
Topics: Antiviral Agents; Drug Delivery Systems; Hepacivirus; Humans; Oligonucleotides
PubMed: 26510815
DOI: 10.4155/fmc.15.144 -
Current Pharmaceutical Biotechnology 2014
Topics: Drug Delivery Systems; Humans; Oligonucleotides; Transfection
PubMed: 25403515
DOI: 10.2174/138920101509141107121143 -
Xenobiotica; the Fate of Foreign... Aug 2022The current regulatory landscape for the development of oligonucleotide drugs may lead companies to perform a variety of small molecule-focussed absorption,...
The current regulatory landscape for the development of oligonucleotide drugs may lead companies to perform a variety of small molecule-focussed absorption, distribution, metabolism and elimination (ADME) studies in support of filing packages. Asking the question, if the current activities are suitable for these modalities and should science-driven decisions on development of such molecules be implemented more in the industry.Challenges and opportunities within oligonucleotide ADME were presented and discussed at the online oligonucleotide ADME workshop (17th and 18th of November 2021). This article summarises the presentations and discussions from the workshop.The following topics were covered: Introduction to Delivery of Antisense RNA Therapeutics (DARTER), Nucleic Acid Therapy Accelerator (NATA) and OligoNova initiatives.Presentation of various oligonucleotide ADME strategies.Update on the Oligonucleotide Safety Working Group (OSWG) pharmacokinetics (PK)/ADME subcommittee's recommendations.Oligonucleotide quantitative whole-body autoradiography (QWBA) hot or not?Multimodal imaging of therapeutic oligonucleotides.
Topics: Oligonucleotides; Pharmaceutical Preparations
PubMed: 36093882
DOI: 10.1080/00498254.2022.2115428 -
Therapeutic Delivery Jul 2013Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent... (Review)
Review
Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake mechanisms and pharmacokinetic properties.
Topics: Animals; Aptamers, Nucleotide; Humans; Ligands; Oligonucleotides; Oligopeptides
PubMed: 23883124
DOI: 10.4155/tde.13.47 -
Science (New York, N.Y.) Apr 2024Therapeutic oligonucleotides are a powerful drug modality with the potential to treat many diseases. The rapidly growing number of therapies that have been approved and... (Review)
Review
Therapeutic oligonucleotides are a powerful drug modality with the potential to treat many diseases. The rapidly growing number of therapies that have been approved and that are in advanced clinical trials will place unprecedented demands on our capacity to manufacture oligonucleotides at scale. Existing methods based on solid-phase phosphoramidite chemistry are limited by their scalability and sustainability, and new approaches are urgently needed to deliver the multiton quantities of oligonucleotides that are required for therapeutic applications. The chemistry community has risen to the challenge by rethinking strategies for oligonucleotide production. Advances in chemical synthesis, biocatalysis, and process engineering technologies are leading to increasingly efficient and selective routes to oligonucleotide sequences. We review these developments, along with remaining challenges and opportunities for innovations that will allow the sustainable manufacture of diverse oligonucleotide products.
Topics: Oligonucleotides; Chemistry Techniques, Synthetic
PubMed: 38603508
DOI: 10.1126/science.adl4015 -
Analytical and Bioanalytical Chemistry Jul 2013Fluorescence imaging coupled with nanotechnology is making possible the development of powerful tools in the biological field for applications such as cellular imaging... (Review)
Review
Fluorescence imaging coupled with nanotechnology is making possible the development of powerful tools in the biological field for applications such as cellular imaging and intracellular messenger RNA monitoring and detection. The delivery of fluorescent probes into cells and tissues is currently receiving growing interest because such molecules, often coupled to nanodimensional materials, can conveniently allow the preparation of small tools to spy on cellular mechanisms with high specificity and sensitivity. The purpose of this review is to provide an exhaustive overview of current research in oligonucleotide optical switches for intracellular sensing with a focus on the engineering methods adopted for these oligonucleotides and the more recent and fascinating techniques for their internalization into living cells. Oligonucleotide optical switches can be defined as specifically designed short nucleic acid molecules capable of turning on or modifying their light emission on molecular interaction with well-defined molecular targets. Molecular beacons, aptamer beacons, hybrid molecular probes, and simpler linear oligonucleotide switches are the most promising optical nanosensors proposed in recent years. The intracellular targets which have been considered for sensing are a plethora of messenger-RNA-expressing cellular proteins and enzymes, or, directly, proteins or small molecules in the case of sensing through aptamer-based switches. Engineering methods, including modification of the oligonucleotide itself with locked nucleic acids, peptide nucleic acids, or L-DNA nucleotides, have been proposed to enhance the stability of nucleases and to prevent false-negative and high background optical signals. Conventional delivery techniques are treated here together with more innovative methods based on the coupling of the switches with nano-objects.
Topics: Animals; Biosensing Techniques; Cells; DNA; Fluorescent Dyes; Humans; Oligonucleotides
PubMed: 23793395
DOI: 10.1007/s00216-013-7086-8 -
Journal of the American Society For... Sep 2020As interests increase in oligonucleotide therapeutics, there has been a greater need for analytical techniques to properly analyze and quantitate these biomolecules.... (Review)
Review
As interests increase in oligonucleotide therapeutics, there has been a greater need for analytical techniques to properly analyze and quantitate these biomolecules. This article looks into some of the existing chromatographic approaches for oligonucleotide analysis, including anion exchange, hydrophilic interaction liquid chromatography, and ion pair chromatography. Some of the key advantages and challenges of these chromatographic techniques are discussed. Colloid formation in mobile phases of alkylamines and fluorinated alcohols, a recently discovered analytical challenge, is discussed. Mass spectrometry is the method of choice to directly obtain structural information about oligonucleotide therapeutics. Mass spectrometry sensitivity challenges are reviewed, including comparison to other oligonucleotide techniques, salt adduction, and the multiple charge state envelope. Ionization of oligonucleotides through the charge residue model, ion evaporation model, and chain ejection model are analyzed. Therapeutic oligonucleotides have to undergo approval from major regulatory agencies, and the impurities and degradation products must be well-characterized to be approved. Current accepted thresholds for oligonucleotide impurities are reported. Aspects of the impurities and degradation products from these types of molecules are discussed as well as optimal analytical strategies to determine oligonucleotide related substances. Finally, ideas are proposed on how the field of oligonucleotide therapeutics may improve to aid in future analysis.
Topics: Chromatography, Liquid; Hydrophobic and Hydrophilic Interactions; Mass Spectrometry; Oligonucleotides
PubMed: 32812756
DOI: 10.1021/jasms.0c00179 -
European Journal of Pharmaceutics and... Oct 2016The potential therapeutic and diagnostic applications of oligonucleotides (ONs) have attracted great attention in recent years. The capability of ONs to selectively... (Review)
Review
The potential therapeutic and diagnostic applications of oligonucleotides (ONs) have attracted great attention in recent years. The capability of ONs to selectively inhibit target genes through antisense and RNA interference mechanisms, without causing un-intended sideeffects has led them to be investigated for various biomedical applications, especially for the treatment of viral diseases and cancer. In recent years, many researchers have focused on enhancing the stability and target specificity of ONs by encapsulating/complexing them with polymers or lipid chains to formulate nanoparticles/nanocomplexes/micelles. Also, chemical modification of nucleic acids has emerged as an alternative to impart stability to ONs against nucleases and other degrading enzymes and proteins found in blood. In addition to chemically modifying the nucleic acids directly, another strategy that has emerged, involves conjugating polymers/peptide/aptamers/antibodies/proteins, preferably to the sense strand (3'end) of siRNAs. Conjugation to the siRNA not only enhances the stability and targeting specificity of the siRNA, but also allows for the development of self-administering siRNA formulations, with a much smaller size than what is usually observed for nanoparticle (∼200nm). This review concentrates mainly on approaches and studies involving ON-conjugates for biomedical applications.
Topics: Gene Silencing; Oligonucleotides
PubMed: 27521696
DOI: 10.1016/j.ejpb.2016.07.024