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Goyenvalle A, Griffith G, Babbs A, et al.. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers, Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Gragoudas ES, Adamis AP, Cunningham ET Jr. et al., Pegaptanib for neovascular age-related macular degeneration, 2-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Federal government websites often end in .gov or .mil. Liu J, Pendergraff H, Narayanannair KJ, et al.. RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression, Allele-selective inhibition of mutant atrophin-1 expression by duplex and single-stranded RNAs. Nanoparticles and liposomal formulations accumulate in the liver, but specific uptake also occurs via, for example, binding to the asialoglycoprotein receptor. Exon inclusion can be achieved by blocking of intronic splicing silencer sequences as for the treatment of SMA.113,114 Isis Pharmaceuticals recently reported promising results for the treatment of SMA in clinical studies.115 Bi-functional SSOs equipped with a tail containing target sites for splicing factors have also been used to enhance specific exon inclusion at weak splice sites.116118 Additional diseases where SSO treatments are also investigated have recently been reviewed.56, Worth considering is also the possibility of targeting multiple sites by the combination of several SSOs,119 or using bispecific antisense sequences targeting different mRNAs from within the same ON.120 An interesting design in this regard was the synthesis of disulfide-linked ONs to allow the delivery of two different SSOs in a 1:1 ratio into the same cell. Alternatively, when miRs are missing they can be replaced by administrating synthetic miR-mimics. Phosphorothioate ONs bind serum proteins, leading to reduced renal clearance and an increased circulation time.6 The uncharged PMO backbone, on the other hand, allows conjugation to positively charged cell-penetrating peptides, which also increase cellular uptake.107 Another interesting approach is the addition of a nuclear localization signal by linking a tri-methylated m3G-cap, which increased the nuclear concentration and splice-correcting effect of an SSO.108 Other modifications like insertion of intercalating ZEN residues have also been tried in order to improve splice correction.109 Incorporation of LNA into 2-O-Me-PS ONs and chemistries like the tricyclo-DNA have also been used with promising results.33 Splice correction by pseudo-exon skipping was recently demonstrated in a mouse model for XLA, the first in vivo example of splice switching in hematopoietic cells.100,101. Bielinska A, Shivdasani RA, Zhang LQ, et al.. Regulation of gene expression with double-stranded phosphorothioate oligonucleotides, Modeling, synthesis, and hybridization properties of (L)-ribonucleic acid, Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer, Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. Elbashir SM, Harborth J, Lendeckel W, et al.. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, Safety and efficacy study of small interfering ribonucleic acid (RNA) molecule (Cand5) to treat wet age-related macular degeneration, {"type":"clinical-trial","attrs":{"text":"NCT00259753","term_id":"NCT00259753"}}, Combination therapy using the small interfering RNA bevasiranib, Sequence- and target-independent angiogenesis suppression by siRNA via TLR3, Preclinical and clinical development of siRNA-based therapeutics. Apart from therapeutical applications where the aptamer is the drug, aptamers have also been used for targeted delivery of ONs. Application number US 08/861,306. Intracellular G-quadruplexes have so far not been targeted by ONs in a therapeutic context, but G-quadruplex formation constitutes an integral part of at least one of the aptamers, which has entered into clinical trials.17 In 1987, TFOs were first demonstrated to bind sequence-specifically, when the Dervan and Hlne laboratories independently reported site-specific cleavage of a DNA target.18,19 TFOs have so far not been studied in the clinics. El-Andaloussi S, Johansson HJ, Lundberg P, et al.. For example, the first-in-class FDA-approved aptamer pegaptanib works by blocking vascular endothelial growth factor (VEGF), preventing it from binding to VEGF receptors on the cell surface,49,123 which in turn inhibits intracellular signaling and blocks neovascularization. ON, oligonucleotide. Palhais B, Praestegaard VS, Sabaratnam R, et al.. Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells. They can block the binding of transcription factors, that is, interfere with the initiation of transcription, or act by stalling RNA polymerases. and transmitted securely. Thus, in 1978 Paul Zamecnik and Mary Stephenson reported in two back-to-back articles in the Proceedings of the National Academy of Sciences U.S.A. that the addition of a 13-mer oligodeoxyribonucleotide could inhibit Rous sarcoma virus in infected cell cultures.23,24 The following year, a publication described that RNase H site-specifically cleaves the RNA strand in RNADNA heteroduplexes,25 thereby demonstrating that antisense therapy can work not only by steric blocking, but also through an enzyme-mediated process. Halperin SA, Van Nest G, Halperin B, et al.. Immunostimulatory Oligonucleotide (ISS ODN) Co-Injection Enhances Protective Antibody Response to Hepatitis B Surface Antigen (HBsAg) and Is Well-Tolerated by Seronegative Individuals. demonstrated that the trimeric form of the N-acetylgalactosamine (GalNAc) was the most optimal targeting moiety for uptake in hepatocytes via this receptor.78 Chemistries used for solid-supported synthesis of ON conjugates for improved delivery and targeting of ON drugs have been reviewed,79 and recently a simplified method to synthesize trimeric GalNAc ligands for siRNA delivery to the liver was reported.80 Cellular uptake and intracellular trafficking of therapeutic ONs have also been frequently reviewed.81 Interesting routes are the delivery of siRNA into the brain by systemic injection of targeted exosomes,82,83 and uptake of siRNAs into the brain following intranasal administration of cell-penetrating peptide-modified nano-micelles.84 Targeting specific organs by aptamers is also an interesting approach further discussed in the aptamer section.85, With the delivery to most organs mainly unsolved, there is so far no approved siRNA-based clinical treatment,86,87 whereas two FDA-approved gapmers have reached the clinic for the treatment of CMV retinitis88 and severe hypercholesterolaemia, respectively.89, miRs are small noncoding RNAs that influence translation through the binding to imperfect, complementary sites on the target mRNA. Halperin SA, Van Nest G, Smith B, et al.. A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Since the first proof of principle with ON-mediated correction of the splicing of a mutated thalassemic, betaglobin intron,43 synthetic antisense ONs have become interesting as possible splice-modulating compounds in a number of diseases, for example, DMD,97 spinal muscular atrophy (SMA),98 familial hypercholesterolemia,99 and X-linked agammaglobulinemia (XLA),100,101 The earliest reported clinical trials with splice-switching ONs (SSOs) have been as treatment of DMD (Fig. Cannata F, Brunet E, Perrouault L, et al.. Triplex-forming oligonucleotide-orthophenanthroline conjugates for efficient targeted genome modification, Gene regulation by antisense transcription, Sequence-selective targeting of duplex DNA by peptide nucleic acids. Also, the phosphorothioate chemistry, which was developed by Fritz Eckstein,5 remains a highly important modification for most of today's ON drugs, since it both confers protection against degradation and aids in the cellular uptake of ONs.6,7 In the 1960s another 2 modification, 2-O-methyl (2-O-Me), was also synthesized in a laboratory for the first time.8 Although this nucleotide exists naturally in certain endogenous RNA species, it serves as an important ingredient in several synthetic, therapeutic ONs. Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. Zammarchi F, de Stanchina E, Bournazou E, et al.. Antitumorigenic potential of STAT3 alternative splicing modulation. A recent major development in molecular biology is the CRISPR-Cas technology for genome editing, first published in 2012.60 This enzymeRNA complex is dependent on two short RNA sequences, which may also be engineered as a single RNA chimera, dual-tracrRNA:crRNA, or guide RNA, serving as a very efficient tool for editing purposes, and such short RNA species can be synthesized as ONs. van Deutekom JC, Janson AA, Ginjaar IB, et al.. Local dystrophin restoration with antisense oligonucleotide PRO051, Development of therapeutic splice-switching oligonucleotides. Bramsen JB, Laursen MB, Damgaard CK, et al.. In 1990, two laboratories independently reported the efficient production of ON aptamers, that is, ONs that bind to a specific target molecule, often a protein, in the absence of hybridization.38,39 The enrichment procedure was called systematic evolution of ligands by exponential enrichment (SELEX). Inducing exon skipping, restoring a malfunctioning splicing pattern, and shifting the ratio between existing splice forms have emerged as possible means to treat a number of genetic diseases. Filed 1991. Very few base modifications are allowed within this DNA gap, in order not to disturb the catalysis.66 In dominant diseases caused by a mutation in a single allele, RNase H degradation can be selectively targeted against the mutated mRNA through ONs binding to (1) the specific point mutation,67 (2) structural differences between wild-type and mutant mRNA,6870 or (3) a single nucleotide polymorphism that is unique to the mutant RNA.71,72, siRNAs are short 2024bp dsRNA ONs with phosphorylated 5 ends and hydroxylated 3 ends with two overhanging nucleotides. Improved silencing properties using small internally segmented interfering RNAs. demonstrated that LNA and ENA (2-O, 4-C-ethylene-bridged nucleic acids) oligomers were able to reduce RNA polymerase and SP1 transcription factor occupancy in the promoter of both the progesterone and androgen receptor genes,143 and LNA-based AGOs were recently reviewed.33, An interesting approach is to combine the TFO and WC binding modes in a clamp-like ON. reported that an LNA-containing tail-clamp version, called bisLNA, in contrast to bisPNA, was able to strand-invade into supercoiled DNA at physiological salt concentrations.145 Like TFOs, bisPNA and pseudo-complementary PNA-ONs together with a donor DNA have been used to induce homologous repair, as reported for a thalassemia-associated beta-globulin mutation.146 Site-directed repair of the dystrophin gene has also been reported, after PNA-ssDNA ON injections into the muscle of mdx mice.147. However, there is room for cautious optimism. Le Doan T, Perrouault L, Praseuth D, et al.. Sequence-specific recognition, photocrosslinking and cleavage of the DNA double helix by an oligo-[alpha]-thymidylate covalently linked to an azidoproflavine derivative, Studies on polynucleotides. From all the attempts to develop ONs into medicines, as depicted in Fig. 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. sharing sensitive information, make sure youre on a federal The landmark discovery of DNA as the hereditary material by Avery et al. In 2001, the first use of CpG ONs in the clinics was reported. This compound was coadministered, in a phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen, as an immunostimulatory phosphorothioate ON adjuvant.46,47 Three years later pegaptanib (brand name: Macugen) became the first FDA-approved aptamer.48 It was used as an antiangiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration and delivered by intravitreous injections. History of oligonucleotide therapeutics. Bestas B, Moreno PM, Blomberg KE, et al.. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model. Redirecting splicing with bifunctional oligonucleotides, Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides, Bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors. (1) Binding to Toll-like receptors (TLRs) in the endosome. Owing to the improved efficacy of current HIV therapies, CMV retinitis no longer constitutes a medical problem for this patient group, and the drug has been withdrawn. Similar to other novel fields, there is a lag phase from the early discoveries until such therapies enter into human studies. Alexopoulou L, Holt AC, Medzhitov R, et al.. The new PMC design is here! Hildebrandt-Eriksen ES, Bagger YZ, Knudsen TB, et al.. A unique therapy for HCV inhibits microRNA-122 in humans and results in HCV RNA suppression in chronically infected chimpanzees: results from primate and first-in-human studies. Turunen MP, Lehtola T, Heinonen SE, et al.. Here the aim is to induce skipping of a mutated exon to restore the reading frame and convert the severe DMD phenotype to the milder Becker dystrophy.102 For this disease two different chemistries have been tried, 2-O-methyl-phosphorothioate RNA (2-O-Me-PS) ONs (Drisapersen; Prosensa) and PMOs (Eterplisen; Sarepta Therapeutics), as earlier reviewed.56,103, SSOs can act through either exon exclusion or exon inclusion mechanisms. An official website of the United States government. Selected through in vitro or cell-based SELEX approaches, a substantial amount of DNA and RNA aptamers have been generated since the early 1990s (Fig. Nielsen TO, Sorensen S, Dagnaes-Hansen F, et al.. (7) Splice switching ON (SSO). In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. Total synthesis of the structural gene for an alanine transfer ribonucleic acid from yeast, Polymer support oligonucleotide synthesis XVIII: use of beta-cyanoethyl-N,N-dialkylamino-/N-morpholino phosphoramidite of deoxynucleosides for the synthesis of DNA fragments simplifying deprotection and isolation of the final product, Automated chemical synthesis of long oligoribonucleotides, Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide, Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide, Walder JAIC, Walder RY (inventor), University of Iowa Research Foundation (assignee). (5) Gapmer AON, inducing RNase H degradation (steric block ONs also exist). Boulware SB, Christensen LA, Thames H, et al.. Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer, Biological activity and biotechnological aspects of peptide nucleic acid, Superior duplex DNA strand invasion by acridine conjugated peptide nucleic acids, Increased stability and specificity through combined hybridization of peptide nucleic acid (PNA) and locked nucleic acid (LNA) to supercoiled plasmids for PNA-anchored Bioplex formation, Sequence-specific inhibition of RNA polymerase III-dependent transcription using Zorro locked nucleic acid (LNA). Pseudo-exon exclusion can be achieved by splice correcting ONs targeting the actual mutation site, a promising approach to restore splicing of, for example, the ironsulfur cluster scaffold, pre-mRNA, or to treat hereditary myopathy with lactic acidosis.104,105 Another strategy is to target an exon splice enhancer sequence in, for example, XLA,100 or in homocystinuria.106, The efficiency of SSOs is highly dependent on the ON chemistry, as well as on the target tissue. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (, GUID:A30B490F-A4F3-4D43-B1AB-AF499CEA6AD2, Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from Pneumococcus type III, Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid, The synthesis of some 5'-thiopentofuranosylpyrimidines, Nucleosides. ONs rich in G-base repeat stretches have been shown to form G-quadruplexes by positioning four G's in a planar conformation (combined WatsonCrick and Hoogsteen base pairing) stabilized by a monovalent cation (Na+ or K+) in the center. Treating diseases through targeting of a specific gene expressed in the liver is appealing because of the easy access of this organ by systemic delivery. However, with regard to hybridization there is yet another binding mode, namely, Hoogsteen binding.16 Thus, a decade after James Watson and Francis Crick published their model of the DNA double helix, Karst Hoogsteen reported a crystal structure in which methylated A and T formed a base pair that had a different geometry from that described by Watson and Crick. in 1944,1 followed by the insightful report on the helical structure of DNA,2 paved the way for our current understanding and use of nucleic acids, including the development of oligonucleotide (ON) therapies. The 1970s is also the decade that witnessed what is generally considered as the birth of antisense therapy. This would fulfill the initial conceptual dream that ON medicines, compared to low molecular traditional drugs as well as to biologics, are much more straightforward to both design and develop. Splicing is a very delicate process, and beside the highly conserved 5 and 3 splice sites in the pre-mRNA, it involves a number of splicing factors interacting with specific target sequences in both exons and introns. 1995, ISIS Pharmaceuticals (assignee). Janssen HL, Reesink HW, Lawitz EJ, et al.. The gap is surrounded by a short stretch of synthetic nucleotides with strong hybridization properties that protect from exonuclease degradation as discussed below. 103. Thus, AGOs must reach the nuclear compartment, access their targets in a chromatin context, and overcome the hybridization between the complementary DNA strands in order to strand-invade. While the structure of G-quadruplexes was delineated already in 1962,129 implications for therapeutic ONs were first noted in 1993.130 In this report, using G-rich antisense ONs, the activity was shown not only to be dependent on the ON sequence, but also to strongly correlate with presence of the G-rich stretches. Antagomirs have been designed as potential therapeutics for the treatment of, for example, hepatitis C infection (anti-miR122),90,91 breast cancer (anti-miR221),92 brain tumors (anti-miR155),93 neurodegenerative disorders,94 and obesity.95 Synthetic miR mimics, like the miR-34-mimicking ON, have already reached clinical studies for the treatment of unresectable liver cancer.96. Rocha CS, Wiklander OP, Larsson L, et al.. RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form, Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron, Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice, Isis Pharmaceuticals reports interim results from ISIS-SMN Rx multiple dose study in children with spinal muscular atrophy, Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts, Correction of disease-associated exon skipping by synthetic exon-specific activators. Induction of splice correction by cell-penetrating peptide nucleic acids, A synthetic snRNA m3G-CAP enhances nuclear delivery of exogenous proteins and nucleic acids. Martinez et al. Brosseau JP, Lucier JF, Lamarche AA, et al.. A common denominator for several of the ON-based therapeutics is the use of the same synthetic nucleotide chemistries, such as the phosphorothioate modification. Systemic administration of a phosphorothioate oligonucleotide with a sequence complementary to p53 for acute myelogenous leukemia and myelodysplastic syndrome: initial results of a phase I trial.

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