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International Journal of Molecular... Nov 2022Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3' UTR of the myotonic dystrophy protein kinase ()... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3' UTR of the myotonic dystrophy protein kinase () gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.
Topics: Mice; Humans; Animals; Myotonic Dystrophy; Myotonin-Protein Kinase; Oligonucleotides, Antisense; Mice, Transgenic; Oligonucleotides; 3' Untranslated Regions; Trinucleotide Repeat Expansion
PubMed: 36362145
DOI: 10.3390/ijms232113359 -
Seminars in Ophthalmology Aug 2021Antisense oligonucleotides (AON) are synthetic single-stranded fragments of nucleic acids that bind to a specific complementary messenger RNA (mRNA) sequence and change...
Antisense oligonucleotides (AON) are synthetic single-stranded fragments of nucleic acids that bind to a specific complementary messenger RNA (mRNA) sequence and change the final gene product. AON were initially approved for treating cytomegalovirus retinitis and have shown promise in treating Mendelian systemic disease. AON are currently being investigated as a treatment modality for many ophthalmic diseases, including inherited retinal disorders (IRD), inflammatory response and wound healing after glaucoma surgery, and macular degeneration. They provide a possible solution to gene therapy for IRD that are not candidates for adeno-associated virus (AAV) delivery. This chapter outlines the historical background of AON and reviews clinical applications and ongoing clinical trials.
Topics: Dependovirus; Genetic Therapy; Humans; Oligonucleotides, Antisense; Retina; Retinal Diseases
PubMed: 34010086
DOI: 10.1080/08820538.2021.1914116 -
Trends in Pharmacological Sciences Nov 2018Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51 to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza as a treatment... (Review)
Review
Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51 to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza as a treatment for spinal muscular atrophy (SMA) - highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cases, the identification and specific removal of 'dispensable' exons by exon-skipping ASOs could potentially bypass lethal mutations in other genes and bring clinical benefits to affected individuals carrying amenable mutations. In this review, we discuss the potential of therapeutic alternative splicing, with a particular focus on targeted exon skipping using Duchenne MD as an example, and speculate on new applications for other inherited rare diseases where redundant or dispensable exons may be amenable to exon-skipping ASO intervention as precision medicine.
Topics: Alternative Splicing; Animals; Exons; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Mutation; Oligonucleotides, Antisense; Precision Medicine
PubMed: 30282590
DOI: 10.1016/j.tips.2018.09.001 -
Drug Discoveries & Therapeutics 2016Therapeutic oligonucleotides are promising technologies. Nevertheless, improvement of their efficacy is an important issue. Introducing this drug delivery system (DDS)... (Review)
Review
Therapeutic oligonucleotides are promising technologies. Nevertheless, improvement of their efficacy is an important issue. Introducing this drug delivery system (DDS) makes for a great enhancement for delivery of oligonucleotides to targeted tissue or cells. The strategy of DDS for therapeutic oligonucleotides is divided into four categories, A) single piece of oligonucleotide, B) oligonucleotide-ligand conjugate, C) oligonucleotide-polymer conjugate, and D) nanoparticle. In this review we will describe those basic concepts, especially for the technology of conjugating ligand. In addition, we developed a new technology, heteroduplex oligonucleotide (HDO), binding ligand-molecule to antisense oligonucleotide indirectly. We also outline α-tocopherol (a natural isomer of vitamin E) conjugated HDO.
Topics: Drug Delivery Systems; Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering; Tocopherols
PubMed: 27890899
DOI: 10.5582/ddt.2016.01065 -
Current Pharmaceutical Design 2015Antisense oligonucleotide therapy is a growing field in cardiac, metabolic, and muscular diseases. This precision therapy allows for treatment of diseases due to... (Review)
Review
Antisense oligonucleotide therapy is a growing field in cardiac, metabolic, and muscular diseases. This precision therapy allows for treatment of diseases due to specific genetic defects. Antisense has few side effects and is relatively long lasting. Some major targets for antisense therapy include hyperglycemia, hyperlipidemia, and hypercholesterolemia. ISIS Pharmaceuticals recently commercialized antisense therapy with Kynamro (Mipomersen) for homozygous familial hypercholesterolemia, opening the door for other antisense oligonucleotides for lowering proteins. Antisense can also be used to increase proteins that are inhibited by mutant exons. Sarepta is testing exon 51 skipping in the mutated dystrophin gene, which if successful will help affected individuals walk, and may help restore some cardiac function. These antisense techniques also could be applied as antisense therapies to overcome gene defects in hypertension, heart disease, muscular defects and metabolic syndrome.
Topics: Cardiovascular Diseases; Exons; Humans; Mutation; Oligonucleotides, Antisense
PubMed: 26234793
DOI: 10.2174/1381612821666150803150402 -
Human Gene Therapy Aug 2015In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various... (Review)
Review
In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism.
Topics: Animals; Genetic Therapy; History, 20th Century; Humans; MicroRNAs; Oligonucleotides, Antisense; RNA Interference; RNA Stability
PubMed: 26160334
DOI: 10.1089/hum.2015.070 -
Blood Nov 2023Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant adult-onset disorder caused by point mutations in the transthyretin (TTR) gene encoding TTR,...
Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant adult-onset disorder caused by point mutations in the transthyretin (TTR) gene encoding TTR, also known as prealbumin. ATTRv survival ranges from 3 to 10 years, and peripheral nervous system and heart are usually the 2 main tissues affected, although central nervous system and eye may also be involved. Because the liver is the main TTR protein secretor organ, it has been the main target of treatments developed these last years, including liver transplantation, which has been shown to significantly increase survival in a subset of patients carrying the so-called "early-onset Val30Met" TTR gene mutation. More recently, treatments targeting hepatic TTR RNA have been developed. Hepatic TTR RNA targeting is performed using RNA interference (RNAi) and antisense oligonucleotide (ASO) technologies involving lipid nanoparticle carriers or N-acetylgalactosamine fragments. RNAi and ASO treatments induce an 80% decrease in TTR liver production for a period of 1 to 12 weeks. ASO and RNAi phase 3 trials in patients with TTR-related polyneuropathy have shown a positive impact on neuropathy clinical scores and quality of life end points, and delayed RNAi treatment negatively affects survival. Clinical trials specifically investigating RNAi therapy in TTR cardiomyopathy are underway. Hepatic RNA targeting has revolutionized ATTRv treatment and may allow for the transforming a fatal disease into a treatable disorder. Because retina and choroid plexus secrete limited quantities of TTR protein, both tissues are now seen as the next targets for fully controlling the disease.
Topics: Adult; Humans; Oligonucleotides, Antisense; RNA Interference; Quality of Life; CRISPR-Cas Systems; Amyloid Neuropathies, Familial; Oligonucleotides; RNA
PubMed: 37624911
DOI: 10.1182/blood.2023019884 -
Bioorganic & Medicinal Chemistry Jan 2023This study was aimed at developing a novel platform for tetravalent conjugation of 4-arm polyethylene glycol (PEG) with an antisense oligonucleotide (ASO). The ASO...
This study was aimed at developing a novel platform for tetravalent conjugation of 4-arm polyethylene glycol (PEG) with an antisense oligonucleotide (ASO). The ASO technology has several limitations, such as low cellular uptake, poor nuclease stability, and short half-life. PEG-conjugated ASOs may result in an improvement in the pharmacokinetic behavior of the drug. Moreover, PEGylation can reduce enzymatic degradation and renal excretion of the conjugates, thereby, increasing its blood stability and retention time. In this study, we successfully synthesized PEG-ASO conjugate consisting of 4-arm-PEG and four molecules of ASO (4-arm-PEG-tetra ASO). Its hybridization ability with complementary RNA, enzymatic stability, and in vitro gene silencing ability were evaluated. No significant difference in hybridization ability was observed between 4-arm-PEG-tetra ASO and the parent ASO. In addition, gene silencing activity of the 4-arm-PEG-tetra ASO was observed in vitro. However, the in vitro activity of the 4-arm-PEG-tetra ASO was slightly reduced as that of the parent ASO. Moreover, the 4-arm-PEG-tetra ASO showed appreciable stability in cellular extract, suggesting that it hybridizes with mRNA in its intact form, without being cleaved in the cell, and exhibits ASO activity.
Topics: Oligonucleotides, Antisense; Polyethylene Glycols; Oligonucleotides; RNA, Messenger
PubMed: 36587552
DOI: 10.1016/j.bmc.2022.117149 -
Journal of Neuromuscular Diseases 2021Research and drug development concerning rare diseases are at the cutting edge of scientific technology. To date, over 7,000 rare diseases have been identified. Despite... (Review)
Review
Research and drug development concerning rare diseases are at the cutting edge of scientific technology. To date, over 7,000 rare diseases have been identified. Despite their individual rarity, 1 in 10 individuals worldwide is affected by a rare condition. For the majority of these diseases, there is no treatment, much less cure; therefore, there is an urgent need for new therapies to extend and improve quality of life for persons who suffer from them. Here we focus specifically on rare neuromuscular diseases. Currently, genetic medicines using short antisense oligonucleotides (ASO) or small interfering ribonucleic acids that target RNA transcripts are achieving spectacular success in treating these diseases. For Duchenne muscular dystrophy (DMD), the state-of-the-art is an exon skipping therapy using an antisense oligonucleotide, which is prototypical of advanced precision medicines. Very recently, golodirsen and viltolarsen, for treatment of DMD patients amenable to skipping exon 53, have been approved by regulatory agencies in the USA and Japan, respectively. Here, we review scientific and clinical progress in developing new oligonucleotide therapeutics for selected rare neuromuscular diseases, discussing their efficacy and limitations.
Topics: Female; Genetic Therapy; Humans; Male; Muscular Dystrophy, Duchenne; Neuromuscular Diseases; Oligonucleotides; Oligonucleotides, Antisense; Quality of Life; Rare Diseases
PubMed: 34092651
DOI: 10.3233/JND-200560 -
Biotechnology and Applied Biochemistry Oct 2021Recently, there is a hopefully tremendous interest in antisense therapeutics for clinical purposes. Single-stranded synthetic antisense oligonucleotides (As-ODNs) with... (Review)
Review
Recently, there is a hopefully tremendous interest in antisense therapeutics for clinical purposes. Single-stranded synthetic antisense oligonucleotides (As-ODNs) with monomers of chemically modified 18-21 deoxynucleotides complement the mRNA sequence in target gene. The target gene expression can be blocked because of created cleavage or disability of the mRNA by binding the As-ODNs to cognate mRNA sequences via sequence-specific hybridization. The idea of antisense therapy has become particular concerning that any sequence longer than a minimal number of nucleotides (17 for DNA and 13 for RNA) can be observed only once within the human genome. The mRNA is omnipresent more probably to manipulate compared to DNA, which results in multiple in vitro and in vivo applications for As-ODNs in the field of regulatory mechanisms of biological processes, cancer, viral infections and hereditary impairments. Although, there are uncertain clinical outcomes on the ability of this approach in treatment procedures despite achieving promising findings based on previous investigations. Accordingly, the efficacy, off-target effects, delivery are issues that should be investigated to obtain satisfactory results. In this review, we will explain the mechanism of action of As-ODNs and various types of modifications and their therapeutic purposes.
Topics: Humans; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 32964539
DOI: 10.1002/bab.2028