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Sheng Wu Gong Cheng Xue Bao = Chinese... May 2018Oligonucleotides are widely used as effective tools to regulate gene expression and drugs for targeted gene therapy. Therefore, they are potentially useful for the... (Review)
Review
Oligonucleotides are widely used as effective tools to regulate gene expression and drugs for targeted gene therapy. Therefore, they are potentially useful for the treatment of viral, tumor and hereditary diseases. Therapeutic oligonucleotides include antisense oligonucleotide, small interference RNA (siRNA), Ribozyme, DNAzyme, anti-gene, CpG, decoy and aptamer. Therapeutic oligonucleotides usually carry certain modifications, such as phosphorothioates, fluoro or locked nucleic acids, to enhance the stability and specificity, and reduce the side-effects, because natural oligonucleotides have poor stability in vivo, low specificity and side effects. Now oligonucleotides are usually manufactured by chemical synthesis, with low purity and high cost. Here, we review a novel thermocyclic reaction for the amplification of oligonucleotides, referred to as Polymerase-endonuclease Amplification Reaction (PEAR) catalyzed by two thermostable enzymes. PEAR is simple, efficient, and stable. Comparing with traditional chemical synthesis, PEAR-based enzymatic production of oligonucleotides could be a robust alternative method for the large-scale production of therapeutic or non-therapeutic oligonucleotides.
Topics: Aptamers, Nucleotide; DNA, Catalytic; Genetic Therapy; Nucleic Acid Amplification Techniques; Oligonucleotides; Oligonucleotides, Antisense; RNA, Catalytic; RNA, Small Interfering
PubMed: 29893074
DOI: 10.13345/j.cjb.170401 -
Neuropharmacology Jul 2017Antisense oligonucleotide (ASO) drugs are an emerging class of therapeutics that have recently demonstrated progress and promise to treat diseases of the central nervous... (Review)
Review
Antisense oligonucleotide (ASO) drugs are an emerging class of therapeutics that have recently demonstrated progress and promise to treat diseases of the central nervous system (CNS). ASOs for a variety of targets and mechanisms are currently being investigated in clinical trials and pre-clinically for a number of CNS diseases. This review examines the available data regarding central ASO delivery, distribution, pharmacokinetics, pharmacodynamics and therapeutic opportunities. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders".
Topics: Animals; Central Nervous System Agents; Central Nervous System Diseases; Drug Delivery Systems; Humans; Oligodeoxyribonucleotides, Antisense
PubMed: 27998711
DOI: 10.1016/j.neuropharm.2016.12.015 -
Drugs Aug 2019Volanesorsen (Waylivra), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA, is being developed by Ionis Pharmaceuticals through its subsidiary...
Volanesorsen (Waylivra), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA, is being developed by Ionis Pharmaceuticals through its subsidiary company, Akcea Therapeutics, to treat familial chylomicronemia syndrome (FCS), hypertriglyceridemia and familial partial lipodystrophy (FPL). In May 2019, volanesorsen was approved in the EU for the treatment of adult patients with FCS based on positive results from the multinational, phase III APPROACH and COMPASS studies. Other clinical trials are ongoing to assess its utility in hypertriglyceridemia, FPL and partial lipodystrophy. This article summarizes the milestones in the development of volanesorsen leading to this first approval as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.
Topics: Apolipoprotein C-III; Clinical Trials, Phase III as Topic; Drug Approval; Europe; Humans; Hyperlipoproteinemia Type I; Hypertriglyceridemia; Lipodystrophy, Familial Partial; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 31301033
DOI: 10.1007/s40265-019-01168-z -
Current Medicinal Chemistry 2017Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle with an additional apolipoprotein, apolipoprotein (a), [apo(a)] attached to apolipoprotein B.... (Review)
Review
Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle with an additional apolipoprotein, apolipoprotein (a), [apo(a)] attached to apolipoprotein B. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) is causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association between Lp(a) concentrations and CVD is still controversial but seems to be continuous and without an obvious threshold Lp(a) level. Circulating concentrations of Lp(a) are genetically determined; desirable levels are < 50 mg/dl. A plasma concentration of 60 mg/dl is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Extended-release niacin is an option for decreasing elevated Lp(a) levels (by ~20-30%) but it is often poorly tolerated. Dietary measures, exercise and lipid-lowering drugs such as statins and ezetimibe are without significant effect. In patients with severe progressive CVD and very high Lp(a) levels, lipoprotein apheresis can decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends mainly on the healthcare reimbursement system. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial that evaluated whether decreasing Lp(a) concentrations translates to clinical benefits. Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by almost 80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon.
Topics: Cardiovascular Diseases; Humans; Lipoproteins; Oligonucleotides, Antisense
PubMed: 28078998
DOI: 10.2174/0929867324666170112110928 -
International Journal of Molecular... Aug 2022The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging... (Review)
Review
The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
Topics: Child; Female; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Neurodegenerative Diseases; Oligonucleotides, Antisense; Proprotein Convertase 9; Quality of Life; RNA; RNA Interference; RNA Splicing; RNA, Messenger
PubMed: 36012138
DOI: 10.3390/ijms23168875 -
Der Nervenarzt Aug 2019Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense... (Review)
Review
Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.
Topics: Genetic Therapy; Humans; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Neurodegenerative Diseases; Oligonucleotides, Antisense
PubMed: 31165208
DOI: 10.1007/s00115-019-0724-4 -
Expert Opinion on Drug Delivery Jun 2019Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems , to... (Review)
Review
INTRODUCTION
Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems , to reach target tissues, and to overcome tissue and cellular barriers. Hyaluronic acid (HA), already utilized in drug delivery and tissue engineering, possess properties that are useful to solve these problems and achieve full potential of oligonucleotide therapeutics.
AREAS COVERED
Complexes of oligonucleotide therapeutics with HA are discussed in terms of interactions providing the complexes formation and genes targeted by the therapeutics to cure diseases such as cancer, atherosclerosis, liver cirrhosis, and inflammation. The achieved therapeutic effects are rationalized as consequences of biodistribution, cell internalization and endosomal escape provided by HA.
EXPERT OPINION
Design of electrostatic, coordination, and hydrophobic interactions as well as covalent conjugation between oligonucleotide drugs, HA macromolecules and intermediate ligands are crucial for carrier-cargo association and dissociation under different conditions to impart oligonucleotides stability , their accumulation in diseased organs, cellular uptake, and dissociation in cytoplasm intact. These are the delivery factors that provides eventual complex formation of oligonucleotide therapeutics with their mRNA, microRNA, or protein targets. Elucidation of the impact of structural parameters of oligonucleotide/HA complexes on their therapeutic effect is important for the future rational design of the delivery agents.
Topics: Drug Delivery Systems; Endosomes; Humans; Hyaluronic Acid; Ligands; Neoplasms; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering; Tissue Distribution
PubMed: 31072142
DOI: 10.1080/17425247.2019.1617693 -
Bioconjugate Chemistry Feb 2019Oligonucleotide-based agents have the potential to treat or cure almost any disease, and are one of the key therapeutic drug classes of the future. Bioconjugated... (Review)
Review
Oligonucleotide-based agents have the potential to treat or cure almost any disease, and are one of the key therapeutic drug classes of the future. Bioconjugated oligonucleotides, a subset of this class, are emerging from basic research and being successfully translated to the clinic. In this Review, we first briefly describe two approaches for inhibiting specific genes using oligonucleotides-antisense DNA (ASO) and RNA interference (RNAi)-followed by a discussion on delivery to cells. We then summarize and analyze recent developments in bioconjugated oligonucleotides including those possessing GalNAc, cell penetrating peptides, α-tocopherol, aptamers, antibodies, cholesterol, squalene, fatty acids, or nucleolipids. These novel conjugates provide a means to enhance tissue targeting, cell internalization, endosomal escape, target binding specificity, resistance to nucleases, and more. We next describe those bioconjugated oligonucleotides approved for patient use or in clinical trials. Finally, we summarize the state of the field, describe current limitations, and discuss future prospects. Bioconjugation chemistry is at the centerpiece of this therapeutic oligonucleotide revolution, and significant opportunities exist for development of new modification chemistries, for mechanistic studies at the chemical-biology interface, and for translating such agents to the clinic.
Topics: Animals; Drug Delivery Systems; Gene Silencing; Humans; Oligonucleotides, Antisense; RNA Interference; RNA, Small Interfering; Transfection
PubMed: 30608140
DOI: 10.1021/acs.bioconjchem.8b00761 -
Methods in Molecular Biology (Clifton,... 2022Cationic cell-penetrating peptides spontaneously associate with negatively charged oligonucleotides to form submicron nanoparticles, so-called polyplexes. Contact with...
Cationic cell-penetrating peptides spontaneously associate with negatively charged oligonucleotides to form submicron nanoparticles, so-called polyplexes. Contact with cells leads to endosomal uptake of these nanoparticles. Oligonucleotide activity critically depends on endosomal release and finally dissociation of polyplexes. Fluorescence provides a highly powerful means to follow the spatial dynamics of oligonucleotide uptake, trafficking and decomplexation, in particular when combined with markers of subcellular compartments that enable a quantitative analysis of colocalization and thereby mapping of trafficking routes. In this chapter, we describe protocols for a highly defined formation of polyplexes. We then point out the use of fluorescent fusion proteins to identify subcellular trafficking compartments and image analysis protocols to obtain quantitative information on trafficking routes and endosomal release.
Topics: Cell-Penetrating Peptides; Endosomes; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 34766291
DOI: 10.1007/978-1-0716-1752-6_13 -
Expert Opinion on Drug Metabolism &... Dec 2023Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for... (Review)
Review
INTRODUCTION
Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.
AREAS COVERED
A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023). ASO PK and PD in animals and humans and modeling approaches including physiologically based (PB) are summarized; and relevance and impacts of PBPK/PD modeling are assessed.
EXPERT OPINION
Allometric scaling and compartmental PK/PD modeling have been successful to predict human ASO PK/PD, addressing most R&D needs. Understanding tissue distribution of ASOs can be crucial for their efficacy and safety especially for intrathecal (IT), pulmonary, or other local routes. PBPK/PD modeling is expected to improve such understanding, for which, efforts have been sporadic. However, developing a PBPK/PD model requires careful review of known biology/pharmacology and thoughtful experimental designs. Resulting models have the potential to predict target/specified tissue exposures and responses in human adults and pediatrics. Ultimately, a PBPK/PD modeling approach can lead to more efficient and rational clinical development, resulting in well-informed decision making and a shortened timeline.
Topics: Adult; Animals; Humans; Child; Oligonucleotides, Antisense; Models, Biological; Tissue Distribution; Lung; Pharmacokinetics
PubMed: 37970635
DOI: 10.1080/17425255.2023.2283524