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Drugs Jun 2024Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in... (Review)
Review
Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in developing novel approaches to integrating Lp(a) into the setting of cardiovascular prevention. Current guidelines advocate universal measurement of Lp(a) levels, with the potential to influence cardiovascular risk assessment and triage of higher-risk patients to use of more intensive preventive therapies. In parallel, considerable activity has been undertaken to develop novel therapeutics with the potential to achieve selective and substantial reductions in Lp(a) levels. Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease.
Topics: Humans; Lipoprotein(a); Cardiovascular Diseases; Oligonucleotides, Antisense; Atherosclerosis; RNA Interference; Oligonucleotides; Animals
PubMed: 38849700
DOI: 10.1007/s40265-024-02046-z -
Advances in Experimental Medicine and... 2023Early cancer identification is crucial for providing patients with safe and timely therapy. Highly dependable and adaptive technologies will be required to detect the... (Review)
Review
Early cancer identification is crucial for providing patients with safe and timely therapy. Highly dependable and adaptive technologies will be required to detect the presence of biological markers for cancer at very low levels in the early stages of tumor formation. These techniques have been shown to be beneficial in encouraging patients to develop early intervention plans, which could lead to an increase in the overall survival rate of cancer patients. Targeted drug delivery (TDD) using aptamer is promising due to its favorable properties. Aptamer is suitable for superior TDD system candidates due to its desirable properties including a high binding affinity and specificity, a low immunogenicity, and a chemical composition that can be simply changed.Due to these properties, aptamer-based TDD application has limited drug side effect along with organ damages. The development of aptasensor has been promising in TDD for cancer cell treatment. There are biomarkers and expressed molecules during cancer cell development; however, only few are addressed in aptamer detection study of those molecules. Its great potential of attachment of binding to specific target molecule made aptamer a reliable recognition element. Because of their unique physical, chemical, and biological features, aptamers have a lot of potential in cancer precision medicine.In this review, we summarized aptamer technology and its application in cancer. This includes advantages properties of aptamer technology over other molecules were thoroughly discussed. In addition, we have also elaborated the application of aptamer as a direct therapeutic function and as a targeted drug delivery molecule (aptasensor) in cancer cells with several examples in preclinical and clinical trials.
Topics: Humans; Aptamers, Nucleotide; Drug Delivery Systems; Neoplasms; Biomarkers; Precision Medicine
PubMed: 35896892
DOI: 10.1007/5584_2022_732 -
Molecules (Basel, Switzerland) Oct 2019G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops... (Review)
Review
G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops length, and localization in the sequence or structure molecularity, G-quadruplexes are highly polymorphic structures showing various folding topologies. They may be formed in the human genome where they are believed to play a pivotal role in the regulation of multiple biological processes such as replication, transcription, and translation. Thus, natural G-quadruplex structures became prospective targets for disease treatment. The fast development of systematic evolution of ligands by exponential enrichment (SELEX) technologies provided a number of G-rich aptamers revealing the potential of G-quadruplex structures as a promising molecular tool targeted toward various biologically important ligands. Because of their high stability, increased cellular uptake, ease of chemical modification, minor production costs, and convenient storage, G-rich aptamers became interesting therapeutic and diagnostic alternatives to antibodies. In this review, we describe the recent advances in the development of G-quadruplex based aptamers by focusing on the therapeutic and diagnostic potential of this exceptional class of nucleic acid structures.
Topics: Aptamers, Nucleotide; Drug Delivery Systems; Early Diagnosis; G-Quadruplexes; Humans
PubMed: 31640176
DOI: 10.3390/molecules24203781 -
Drugs Mar 2017Spinal muscular atrophy (SMA) is a rare autosomal recessive disorder characterized by muscle atrophy and weakness resulting from motor neuron degeneration in the spinal... (Review)
Review
Spinal muscular atrophy (SMA) is a rare autosomal recessive disorder characterized by muscle atrophy and weakness resulting from motor neuron degeneration in the spinal cord and brainstem. It is most commonly caused by insufficient levels of survival motor neuron (SMN) protein (which is critical for motor neuron maintenance) secondary to deletions or mutations in the SMN1 gene. Nusinersen (SPINRAZAâ„¢) is a modified antisense oligonucleotide that binds to a specific sequence in the intron, downstream of exon 7 on the pre-messenger ribonucleic acid (pre-mRNA) of the SMN2 gene. This modulates the splicing of the SMN2 mRNA transcript to include exon 7, thereby increasing the production of full-length SMN protein. Nusinersen is approved in the USA for intrathecal use in paediatric and adult patients with SMA. Regulatory assessments for nusinersen as a treatment for SMA are underway in the EU and several other countries. This article summarizes the milestones in the development of nusinersen leading to this first approval for SMA in paediatric and adult patients.
Topics: Animals; Drug Approval; Humans; Muscular Atrophy, Spinal; Oligonucleotides; Oligonucleotides, Antisense; United States
PubMed: 28229309
DOI: 10.1007/s40265-017-0711-7 -
Mini Reviews in Medicinal Chemistry 2016Many potent DNA aptamers are known to contain a G-quadruplex (G4) core. Structures and applications of the majority of such aptamers have been reviewed previously. The... (Review)
Review
Many potent DNA aptamers are known to contain a G-quadruplex (G4) core. Structures and applications of the majority of such aptamers have been reviewed previously. The present review focuses on the design and optimization of G4 aptamers. General features of bioactive G4s are analyzed, and the main strategies for construction of aptamers with desired properties and topologies, including modular assembly, control of an aptamer folding and some others, are outlined. Chemical modification as a method for post-SELEX G4 aptamer optimization is also discussed, and the effects of loop and core modifications are compared. Particular attention is paid to the emerging trends, such as the development of genomic G4- inspired aptamers and the combinatorial approaches which aim to find a balance between rational design and selection.
Topics: Animals; Aptamers, Nucleotide; G-Quadruplexes; Humans
PubMed: 26996618
DOI: 10.2174/1389557516666160321114715 -
Chembiochem : a European Journal of... Mar 2023The use of polymerase enzymes in biotechnology has allowed us to gain unprecedented control over the manipulation of DNA, opening up new and exciting applications in... (Review)
Review
The use of polymerase enzymes in biotechnology has allowed us to gain unprecedented control over the manipulation of DNA, opening up new and exciting applications in areas such as biosensing, polynucleotide synthesis, and DNA storage, aptamer development and DNA-nanotechnology. One of the most intriguing enzymes which has gained prominence in the last decade is terminal deoxynucleotidyl transferase (TdT), which is one of the only polymerase enzymes capable of catalysing the template independent stepwise addition of nucleotides onto an oligonucleotide chain. This unique enzyme has seen a significant increase in a variety of different applications. In this review, we give a comprehensive discussion of the unique properties and applications of TdT as a biotechnology tool, and the application in the enzymatic synthesis of poly/oligonucleotides. Finally, we look at the increasing role of TdT enzyme in biosensing, DNA storage, synthesis of DNA nanostructures and aptamer development, and give a future outlook for this technology.
Topics: DNA Nucleotidylexotransferase; DNA-Directed DNA Polymerase; DNA; Oligonucleotides; Biotechnology
PubMed: 36342345
DOI: 10.1002/cbic.202200510 -
Nihon Yakurigaku Zasshi. Folia... Jun 2016
Topics: Aptamers, Nucleotide; Clinical Trials as Topic; Molecular Targeted Therapy
PubMed: 27301311
DOI: 10.1254/fpj.147.362 -
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 -
ACS Chemical Biology Oct 2023New technologies are required to combat the challenges faced with manufacturing commercial quantities of oligonucleotide drug substances which are required for treating...
New technologies are required to combat the challenges faced with manufacturing commercial quantities of oligonucleotide drug substances which are required for treating large patient populations. Herein we report a convergent biocatalytic synthesis strategy for an Alnylam model siRNA. The siRNA chemical structure includes several of the unnatural modifications and conjugations typical of siRNA drug substances. Using Almac's 3-2-3-2 hybrid RNA ligase enzyme strategy that sequentially ligates short oligonucleotide fragments (blockmers), the target siRNA was produced to high purity at 1 mM concentration. Additional strategies were investigated including the use of polynucleotide kinase phosphorylation and the use of crude blockmer starting materials without chromatographic purification. These findings highlight a path toward a convergent synthesis of siRNAs for large-scale manufacture marrying both enzymatic liquid and classical solid-phase synthesis.
Topics: Humans; RNA, Small Interfering; Biocatalysis; Oligonucleotides; Phosphorylation
PubMed: 37061926
DOI: 10.1021/acschembio.3c00071 -
Trends in Plant Science Mar 2023Our knowledge of cell- and tissue-specific quantification of phytohormones is heavily reliant on laborious mass spectrometry techniques. Genetically encoded biosensors... (Review)
Review
Our knowledge of cell- and tissue-specific quantification of phytohormones is heavily reliant on laborious mass spectrometry techniques. Genetically encoded biosensors have allowed spatial and some temporal quantification of phytohormones intracellularly, but there is still limited information on their intercellular distributions. Here, we review nucleic acid aptamers as an emerging biosensing platform for the detection and quantification of analytes with high affinity and specificity. Options for DNA aptamer technology are explained through selection, sequencing analysis and techniques for evaluating affinity and specificity, and we focus on previously developed DNA aptamers against various plant analytes. We suggest how these tools might be applied in planta for quantification of molecules of interest both intracellularly and intercellularly.
Topics: Nucleic Acids; Plant Growth Regulators; Aptamers, Nucleotide; Biosensing Techniques; Plants; Biology
PubMed: 36357246
DOI: 10.1016/j.tplants.2022.10.002