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Nucleic Acid Therapeutics

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https://www.readbyqxmd.com/read/27827561/a-novel-pegylation-method-for-improving-the-pharmacokinetic-properties-of-anti-interleukin-17a-rna-aptamers
#1
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/27763826/anti-hiv-activities-of-intramolecular-g4-and-non-g4-oligonucleotides
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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/27629437/four-novel-splice-switch-reporter-cell-lines-distinct-impact-of-oligonucleotide-chemistry-and-delivery-vector-on-biological-activity
#8
Cristina S J Rocha, Karin E Lundin, Mark A Behlke, Rula Zain, Samir El Andaloussi, C I Edvard Smith
New advances in oligonucleotide (ON) chemistry emerge continuously, and over the last few years, several aspects of ON delivery have been improved. However, clear knowledge regarding how certain chemistries behave alone, or in combination with various delivery vectors, is limited. Moreover, characterization is frequently limited to a single reporter cell line and, when different cell types are studied, experiments are commonly not carried out under similar conditions, hampering comparative analysis. To address this, we have developed a small "tissue" library of new, stable, pLuc/705 splice-switching reporter cell lines (named HuH7_705, U-2 OS_705, C2C12_705, and Neuro-2a_705)...
September 15, 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
#9
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/27548631/the-polarization-of-m2b-monocytes-in-cultures-of-burn-patient-peripheral-cd14-cells-treated-with-a-selected-human-ccl1-antisense-oligodeoxynucleotide
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27454558/inhibition-of-mir-21-by-3-5-serinyl-capped-2-o-methyl-rna-interspersed-with-2-o-2-amino-3-methoxypropyl-uridine-units
#13
Smita Nahar, Venubabu Kotikam, Vaijayanti A Kumar, Souvik Maiti
miRNAs are highly conserved class of small ncRNAs whose involvement in human pathophysiologies is extensively investigated. MiR-21 is a well established oncogenic miRNA whose deregulation plays a significant role in onset and progression of cancer. The need of novel approaches to downregulate miR-21 is rapidly expanding. Potent inhibition of miR-21 is achieved by chemically modified 2'-O-methyl RNA oligonucleotide. The serinol capping at 3' and 5'ends and the interspersed 2'-O-(R-2-amino-3-methoxypropyl) uridine units enhance the nuclease resistance and efficacy of 2'-O-methyl RNA for the inhibition of miR-21...
October 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27399870/terminal-duplex-stability-and-nucleotide-identity-differentially-control-sirna-loading-and-activity-in-rna-interference
#14
Phillip A Angart, Rebecca J Carlson, Kwasi Adu-Berchie, S Patrick Walton
Efficient short interfering RNA (siRNA)-mediated gene silencing requires selection of a sequence that is complementary to the intended target and possesses sequence and structural features that encourage favorable functional interactions with the RNA interference (RNAi) pathway proteins. In this study, we investigated how terminal sequence and structural characteristics of siRNAs contribute to siRNA strand loading and silencing activity and how these characteristics ultimately result in a functionally asymmetric duplex in cultured HeLa cells...
October 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27500826/truncation-and-mutation-of-a-transferrin-receptor-aptamer-enhance-binding-affinity
#15
Joanna Macdonald, Patrick Houghton, Dongxi Xiang, Wei Duan, Sarah Shigdar
Aptamers are proving their utility in a number of applications. However, to be easily functionalized, their structure needs to be simplified. Therefore, we sought to truncate a 50-nucleotide aptamer specific to the transferrin receptor to its smallest functional unit using rational engineering of the predicted two-dimensional structure of the longer parent sequence. In addition, mutations were introduced into the binding loop to determine their effect on the selectivity of the aptamers. These base mutations enhanced the binding affinity of the aptamer, while retaining its specificity...
August 8, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27500733/disposition-and-pharmacokinetics-of-a-galnac3-conjugated-antisense-oligonucleotide-targeting-human-lipoprotein-a-in-monkeys
#16
Rosie Z Yu, Rudy Gunawan, Noah Post, Thomas Zanardi, Shannon Hall, Jennifer Burkey, Tae-Won Kim, Mark J Graham, Thazha P Prakash, Punit P Seth, Eric E Swayze, Richard S Geary, Scott P Henry, Yanfeng Wang
Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc3-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching Cmax, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks)...
August 8, 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27500925/dieter-c-gruenert-phd-1949-2016
#17
Petra Disterer, Mark A Kay, Graham C Parker
No abstract text is available yet for this article.
August 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27228357/in-vitro-gene-silencing-of-the-fish-microsporidian-heterosporis-saurida-by-rna-interference
#18
Mona Saleh, Gokhlesh Kumar, Abdel-Azeem Abdel-Baki, Mohamed A Dkhil, Mansour El-Matbouli, Saleh Al-Quraishy
Heterosporis saurida, a microsporidian parasite of lizardfish, Saurida undosquamis, causes severe economic losses in marine aquaculture. Among the novel approaches being explored for treatment of parasitic infections in aquaculture is small interfering RNA molecules. The aim of the present study was to investigate the efficiency of using siRNA to knock down expression of specific genes of H. saurida in vitro. For this purpose, siRNAs specific for ATP/ADP antiporter 1 and methionine aminopeptidase II genes were designed and tested using a previously developed in vitro cultivation model...
August 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27140858/effects-of-repeated-complement-activation-associated-with-chronic-treatment-of-cynomolgus-monkeys-with-2-o-methoxyethyl-modified-antisense-oligonucleotide
#19
Lijiang Shen, Jeffrey A Engelhardt, Gene Hung, Jenna Yee, Rie Kikkawa, John Matson, Bryan Tayefeh, Todd Machemer, Patricia C Giclas, Scott P Henry
The effects of repeated complement activation in cynomolgus monkeys after chronic antisense oligonucleotide (ASO) treatment were evaluated by using ISIS 104838, a representative 2'-O-methoxyethyl (2'-MOE) modified ASO. The treatment was up to 9 months with a total weekly dose of 30 mg/kg, given either as daily [4.3 mg/kg/day, subcutaneous (s.c.) injection] or once weekly [30 mg/kg, either as s.c. injection or 30-min intravenous (i.v.) infusion]. Acute elevations of complement split products (Bb and C3a) and a transient decrease in C3 occurred after the first dose and were drug plasma concentration dependent...
August 2016: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27123752/single-stranded-silencing-rnas-hit-rate-and-chemical-modification
#20
Hannah M Pendergraff, Alexandre J Debacker, Jonathan K Watts
Single-stranded silencing RNAs (ss-siRNAs) are chemically modified single-stranded oligomers that engage the RNA interference machinery normally used by duplex RNAs to silence gene expression. ss-siRNAs have the potential to combine advantages of antisense oligonucleotides and siRNAs. Previous work has explored the chemistry of the phosphate and the oligonucleotide body. We now describe the process of attempting to develop and optimize ss-siRNAs based on five active siRNA duplexes. Three of the sequences failed to show any activity as ss-siRNAs, and in two of those cases the ss-siRNAs showed significantly increased toxicity relative to the parent duplexes...
August 2016: Nucleic Acid Therapeutics
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