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Nucleic Acid Therapeutics

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https://www.readbyqxmd.com/read/28080251/tetrahedral-dna-nanoparticle-vector-for-intracellular-delivery-of-targeted-peptide-nucleic-acid-antisense-agents-to-restore-antibiotic-sensitivity-in-cefotaxime-resistant-escherichia-coli
#1
John Benedict Readman, George Dickson, Nick G Coldham
The bacterial cell wall presents a barrier to the uptake of unmodified synthetic antisense oligonucleotides, such as peptide nucleic acids, and so is one of the greatest obstacles to the development of their use as therapeutic anti-bacterial agents. Cell-penetrating peptides have been covalently attached to antisense agents, to facilitate penetration of the bacterial cell wall and deliver their cargo into the cytoplasm. Although they are an effective vector for antisense oligonucleotides, they are not specific for bacterial cells and can exhibit growth inhibitory properties at higher doses...
January 12, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28080221/molecular-mechanisms-of-antisense-oligonucleotides
#2
Stanley T Crooke
In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals...
January 12, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051352/antisense-oligonucleotides-targeting-raf-1-block-japanese-encephalitis-virus-in-vitro-and-in-vivo
#3
Li Zhang, Qingjun Li, Xiaoran Ding, Bo Zhang, Qiling Zhang, Xinyan Qu, Yujia Huo, Jing Yang, Shengqi Wang
Japanese encephalitis virus (JEV) infections represent a major health concern in Southeast Asia since no effective treatments are available. Recently, several reports have demonstrated that inhibition of certain host cell proteins prevents viral infection. Raf-1 kinase is a central component of many signaling pathways involved in normal cell growth and oncogenic transformation, and Ras/Raf/ERK signaling activation has been observed during viral infections (including JEV infection). In this study, Raf-1 was confirmed to be upregulated by JEV infection, which suggested that Raf-1 might be important for JEV infection and might be a target for novel anti-JEV drugs...
January 4, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051347/-in-house-production-of-single-stranded-oligodeoxyribonucleotides
#4
Allan R D Nunes, Suely F Chavante, Hugo A O Rocha, Daniel C F Lanza
The most widely used technique for the production of DNA aptamers/oligonucleotides is chemical synthesis. Despite its effectiveness, this technique cannot be performed "in house", making the user fully dependent on a supplier. In this work, we present a simplified method by which it is possible to enzymatically produce DNA aptamers "in house". This new method uses the rolling circle replication followed by a unique cleavage step using the SchI endonuclease. Potentially, any oligonucleotide can be produced by the enzymatic method proposed in this study...
January 4, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051346/a-conjugate-of-two-tpa-binding-rna-aptamers-efficiently-inhibits-fibrinolysis
#5
Nils Bjerregaard, Daniel M Dupont, Peter A Andreasen
Uncontrolled bleeding is a major cause of mortality. Lysine analogues are routinely used in the management of bleeding, but several studies indicate a risk of serious detrimental effects upon their administration. In this study, we report a bivalent conjugate "3218" of two RNA aptamers selected for binding to the serine protease tissue-type plasminogen activator (tPA), the principal initiator of fibrinolysis in mammals. The constituent monomeric aptamers, K32v2 and K18v2, were previously demonstrated to weakly inhibit fibrinolysis...
January 4, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28005462/recognition-of-c9orf72-mutant-rna-by-single-stranded-silencing-rnas
#6
Jiaxin Hu, Frank Rigo, Thazha P Prakash, David R Corey
Mutations within the chromosome 9 open reading frame 72 (c9orf72) gene are associated with both familial amyotrophic lateral sclerosis and frontotemporal dementia. The mutation leads to an expanded GGGGCC hexanucleotide repeat within the first intron of c9orf72 and an expanded CCCCGG repeat within a corresponding antisense transcript. Both the mutant intronic and antisense RNAs have been implicated in disease. We have previously reported that duplex RNAs complementary to the repeats can recognize disease-causing RNA and block detection of nuclear foci formed by the mutant transcripts...
December 22, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27929755/fda-approves-eteplirsen-for-duchenne-muscular-dystrophy-the-next-chapter-in-the-eteplirsen-saga
#7
Annemieke Aartsma-Rus, Arthur M Krieg
No abstract text is available yet for this article.
December 8, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27923110/impact-of-oligonucleotide-structure-chemistry-and-delivery-method-on-in-vitro-cytotoxicity
#8
Maja M Janas, Yongfeng Jiang, Mark K Schlegel, Scott Waldron, Satya Kuchimanchi, Scott A Barros
Single-stranded (ss) 2'-fluoro (2'-F)-modified oligonucleotides (ONs) with a full phosphorothioate (PS) backbone have been reported to be cytotoxic and cause DNA double-strand breaks (DSBs) when transfected into HeLa cells. However, the molecular determinants of these effects have not been fully explored. In this study, we investigated the impact of ON structure, chemistry, delivery method, and cell type on in vitro cytotoxicity and DSBs. We found that ss PS-ONs were more cytotoxic than double-stranded (ds) PS-ONs, irrespective of the 2'-ribose chemistry, inclusive of the 2'-F modification...
December 6, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27923103/noninvasive-microsurgery-using-aptamer-functionalized-magnetic-microdisks-for-tumor-cell-eradication
#9
Tatiana N Zamay, Galina S Zamay, Irina V Belyanina, Sergey S Zamay, Valery V Denisenko, Olga S Kolovskaya, Tatiana I Ivanchenko, Valentina L Grigorieva, Irina V Garanzha, Dmitry V Veprintsev, Yury E Glazyrin, Alexandr V Shabanov, Viktor Y Prinz, Vladimir A Seleznev, Alexey E Sokolov, Vladimir S Prokopenko, Petr D Kim, Ana Gargaun, Maxim V Berezovski, Anna S Zamay
Magnetomechanical cell disruption using nano- and microsized structures is a promising biomedical technology used for noninvasive elimination of diseased cells. It applies alternating magnetic field (AMF) for ferromagnetic microdisks making them oscillate and causing cell membrane disruption with cell death followed by apoptosis. In this study, we functionalized the magnetic microdisks with cell-binding DNA aptamers and guided the microdisks to recognize cancerous cells in a mouse tumor in vivo. Only 10 min of the treatment with a 100 Hz AMF was enough to eliminate cancer cells from a malignant tumor...
December 6, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27827561/a-novel-pegylation-method-for-improving-the-pharmacokinetic-properties-of-anti-interleukin-17a-rna-aptamers
#10
Kazuhiko Haruta, Natsuki Otaki, Masakazu Nagamine, Tomoyoshi Kayo, Asako Sasaki, Shinsuke Hiramoto, Masayuki Takahashi, Kuniyoshi Hota, Hideaki Sato, Hiroaki Yamazaki
The obstacles to the development of therapeutic aptamers for systemic inflammatory diseases, such as nuclease degradation and renal clearance, have not been fully overcome. Here, we report a novel PEGylation method, sbC-PEGylation, which improves the pharmacokinetic properties of RNA aptamers that act against interleukin-17A (IL-17A) in mice and monkeys. sbC-PEGylated aptamers were synthesized by coupling the symmetrical branching molecule 2-cyanoethyl-N,N-diisopropyl phosphoroamidite to the 5' end of the aptamer, before conjugating two polyethylene glycol (PEG) molecules to the aptamer...
November 9, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27658045/antisense-oligonucleotides-modulating-activation-of-a-nonsense-mediated-rna-decay-switch-exon-in-the-atm-gene
#11
Jana Kralovicova, Pedro M D Moreno, Nicholas C P Cross, Ana Paula Pêgo, Igor Vorechovsky
ATM (ataxia-telangiectasia, mutated) is an important cancer susceptibility gene that encodes a key apical kinase in the DNA damage response pathway. ATM mutations in the germ line result in ataxia-telangiectasia (A-T), a rare genetic syndrome associated with hypersensitivity to double-strand DNA breaks and predisposition to lymphoid malignancies. ATM expression is limited by a tightly regulated nonsense-mediated RNA decay (NMD) switch exon (termed NSE) located in intron 28. In this study, we identify antisense oligonucleotides that modulate NSE inclusion in mature transcripts by systematically targeting the entire 3...
December 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27763826/anti-hiv-activities-of-intramolecular-g4-and-non-g4-oligonucleotides
#12
Maria Prokofjeva, Vladimir Tsvetkov, Dmitry Basmanov, Anna Varizhuk, Maria Lagarkova, Igor Smirnov, Kirill Prusakov, Dmitry Klinov, Vladimir Prassolov, Galina Pozmogova, Sergey N Mikhailov
New natural and chemically modified DNA aptamers that inhibit HIV-1 activity at submicromolar concentrations (presumably via preventing viral entry into target cells) are reported. The new DNA aptamers were developed based on known intramolecular G-quadruplexes (G4s) that were functionally unrelated to HIV inhibition [the thrombin-binding aptamer and the fragment of the human oncogene promoter (Bcl2)]. The majority of previously described DNA inhibitors of HIV infection adopt intermolecular structures, and thus their folding variability represents an obvious disadvantage...
October 20, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27763825/in-vitro-dose-studies-on-chitosan-nanoplexes-for-microrna-delivery-in-breast-cancer-cells
#13
Kubra Kaban, Emine Salva, Julide Akbuga
Changes in microRNA (miRNA) expression levels that play important roles in regulation lead to many pathological events such as cancer. The miR-200 family is an important target in cancer therapy. The aim of this study is to equilibrate endogenous levels between cancer and noncancerous cells to prevent serious side effects of miR-200c- and miR-141-like metastatic colonization. For the first time, the characterization of miR-200c and miR-141 cluster containing chitosan nanoplexes was shown, and the optimization of miRNA expression levels by conducting dose studies in breast cancer cell lines was made...
October 20, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27754762/a-cholecystokinin-b-receptor-specific-dna-aptamer-for-targeting-pancreatic-ductal-adenocarcinoma
#14
Gary A Clawson, Thomas Abraham, Weihua Pan, Xiaomeng Tang, Samuel S Linton, Christopher O McGovern, Welley S Loc, Jill P Smith, Peter J Butler, Mark Kester, James H Adair, Gail L Matters
Pancreatic ductal adenocarcinomas (PDACs) constitutively express the G-protein-coupled cholecystokinin B receptor (CCKBR). In this study, we identified DNA aptamers (APs) that bind to the CCKBR and describe their characterization and targeting efficacy. Using dual SELEX selection against "exposed" CCKBR peptides and CCKBR-expressing PDAC cells, a pool of DNA APs was identified. Further downselection was based on predicted structures and properties, and we selected eight APs for initial characterizations. The APs bound specifically to the CCKBR, and we showed not only that they did not stimulate proliferation of PDAC cell lines but rather inhibited their proliferation...
October 18, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27753537/distribution-and-penetration-of-intracerebroventricularly-administered-2-omeps-oligonucleotide-in-the-mouse-brain
#15
João Casaca-Carreira, Yasin Temel, Iñaki Larrakoetxea, Ali Jahanshahi
Antisense oligonucleotide (AON) therapy is emerging as a potential treatment strategy for neurodegenerative diseases, such as spinal muscular atrophy, Huntington's disease, and amyotrophic lateral sclerosis. AONs function at the cellular level by, for example, direct interference with the expression of gene products or the molecular activation of neuroprotective pathways. However, AON therapy faces a major obstacle limiting its clinical application for central nervous system (CNS) disorders: the blood-brain barrier...
October 18, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27736370/in-vitro-evaluation-of-aptamer-based-reversible-inhibition-of-anticoagulant-activated-protein-c-as-a-novel-supportive-hemostatic-approach
#16
Nasim Shahidi Hamedani, Heiko Rühl, Julia Janina Zimmermann, Tim Heiseler, Johannes Oldenburg, Günter Mayer, Bernd Pötzsch, Jens Müller
Activated protein C (APC) is a critical regulator of thrombin formation and thereby protects against thrombosis. On the other hand, overwhelming formation of APC increases the risk of bleeding such as in trauma-induced coagulopathy. Thus, pharmacological inhibition of APC activity may improve blood clottability in certain clinical situations. In this study, we demonstrate that the DNA aptamer HS02-52G binds with fast onset (1.118 ± 0.013 × 10(5) M(-1) s(-1)) to APC and possesses a long residence time of 13...
October 13, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27736306/aptamers-promising-tools-for-the-detection-of-circulating-tumor-cells
#17
Eman M Hassan, William G Willmore, Maria C DeRosa
Circulating tumor cells (CTCs) are cells that shed from a primary tumor and freely circulate in the blood, retaining the ability to initiate metastasis and form a secondary tumor in distant organs in the body. CTCs reflect the molecular profile of the primary tumor, therefore studying CTCs can allow for an understanding of the mechanism of metastasis, and an opportunity to monitor the prognosis of cancer. Unfortunately, the detection of CTCs is a considerable challenge due to their low abundance in the bloodstream and the lack of consistent markers present to recognize these cells...
October 13, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27548631/the-polarization-of-m2b-monocytes-in-cultures-of-burn-patient-peripheral-cd14-cells-treated-with-a-selected-human-ccl1-antisense-oligodeoxynucleotide
#18
Ichiaki Ito, Kamlesh K Bhopale, Tomoki Nishiguchi, Jong O Lee, David N Herndon, Sumihiro Suzuki, Lawrence C Sowers, Fujio Suzuki, Makiko Kobayashi
M2b macrophages (Mφ) play a major role in the increased susceptibility of subacutely burned patients, to sepsis stemming from enterococcal translocation. Certain opportunistic infections in severely burned mice have been controlled by murine CCL1 antisense oligodeoxynucleotide (ODN), a specific polarizer of mouse M2bMφ. In the present study, we have screened CCL1 antisense ODN, which is active against human M2bMφ. Among the 20 CCL1 antisense ODNs synthesized in our laboratory, HCA-11 was shown to be the most active polarizer for human CCL1(+)CD163(+)CD14(+) cells...
October 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27548508/identification-of-a-nucleoporin358-specific-rna-aptamer-for-use-as-a-nucleus-targeting-liposomal-delivery-system
#19
Garima Shrivastava, Mamoru Hyodo, Shige H Yoshimura, Hidetaka Akita, Hideyoshi Harashima
An active targeting drug delivery system that targets the nucleus could solve the problem of the treatment of genetic disorders through gene delivery, but it has met with limited success. The purpose of this study was to establish an RNA aptamer-modified nucleus-targeting liposomal carrier system referred to as NupApt-liposomes. RNA aptamers against the Nup358 protein are prepared using a newly established Protein SELEX method. After confirming aptamer binding to the recombinant protein, an aptamer-lipid conjugate (Apt-PEG-DSPE) was prepared...
October 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27463680/antisense-oligonucleotides-targeting-influenza-a-segment-8-genomic-rna-inhibit-viral-replication
#20
Elzbieta Lenartowicz, Aitor Nogales, Elzbieta Kierzek, Ryszard Kierzek, Luis Martínez-Sobrido, Douglas H Turner
Influenza A virus (IAV) affects 5%-10% of the world's population every year. Through genome changes, many IAV strains develop resistance to currently available anti-influenza therapeutics. Therefore, there is an urgent need to find new targets for therapeutics against this important human respiratory pathogen. In this study, 2'-O-methyl and locked nucleic acid antisense oligonucleotides (ASOs) were designed to target internal regions of influenza A/California/04/2009 (H1N1) genomic viral RNA segment 8 (vRNA8) based on a base-pairing model of vRNA8...
October 2016: Nucleic Acid Therapeutics
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