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Nucleic Acid Therapeutics

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https://www.readbyqxmd.com/read/28609186/recommendations-of-the-oligonucleotide-safety-working-group-s-formulated-oligonucleotide-subcommittee-for-the-safety-assessment-of-formulated-oligonucleotide-based-therapeutics
#1
Jennifer L Marlowe, Violetta Akopian, Priya Karmali, Douglas Kornbrust, Jennifer Lockridge, Sean Semple
The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development...
June 13, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28605247/the-distinct-and-cooperative-roles-of-toll-like-receptor-9-and-receptor-for-advanced-glycation-end-products-in-modulating-in-vivo-inflammatory-responses-to-select-cpg-and-non-cpg-oligonucleotides
#2
Suzanne Paz, Jill Hsiao, Patrick Cauntay, Armand Soriano, Lawrence Bai, Todd Machemer, Xiaokun Xiao, Shuling Guo, Gene Hung, Husam Younis, C Frank Bennett, Scott Henry, Theodore J Yun, Sébastien Burel
Antisense oligonucleotides (ASOs) are widely accepted therapeutic agents that suppress RNA transcription. While the majority of ASOs are well tolerated in vivo, few sequences trigger inflammatory responses in absence of conventional CpG motifs. In this study, we identified non-CpG oligodeoxy-nucleotide (ODN) capable of triggering an inflammatory response resulting in B cell and macrophage activation in a MyD88- and TLR9-dependent manner. In addition, we found the receptor for advance glycation end product (RAGE) receptor to be involved in the initiation of inflammatory response to suboptimal concentrations of both CpG- and non-CpG-containing ODNs...
June 12, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28541820/assessment-of-the-effects-of-2-methoxyethyl-antisense-oligonucleotides-on-platelet-count-in-cynomolgus-nonhuman-primates
#3
Scott P Henry, Padmakumar Narayanan, Lijiang Shen, Sanjay Bhanot, Husam S Younis, Sebastien A Burel
Decreases in platelet (PLT) counts observed in nonhuman primates (NHPs) given 2'-O-methoxyethyl modified antisense inhibitors (2'-MOE ASOs) have been reported, but the incidence and severity of the change vary considerably between sequences, studies, and animals. This article will broadly illustrate the spectrum of effects on PLT count in NHPs. From queries of an NHP safety database representing over 102 independent 2'-MOE ASOs, from 61 studies and >2200 NHPs, two patterns of PLT changes emerged. The first is a consistent and reproducible decrease in group mean values, observed with about 30% of the compounds, in which PLT count typically remains ≥150K cells/μL...
May 25, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28448194/co-administration-of-an-excipient-oligonucleotide-helps-delineate-pathways-of-productive-and-nonproductive-uptake-of-phosphorothioate-antisense-oligonucleotides-in-the-liver
#4
Aaron J Donner, Edward V Wancewicz, Heather M Murray, Sarah Greenlee, Noah Post, Melanie Bell, Walt F Lima, Eric E Swayze, Punit P Seth
Phosphorothioate (PS) modified antisense oligonucleotides (ASOs) have progressed rapidly in the clinic for treating a variety of disease indications. We previously demonstrated that the activity of PS ASOs in the liver can be enhanced by co-infusion of an excipient oligonucleotide (EON). It was posited that the EON saturates a nonproductive uptake pathway(s) thereby permitting accumulation of the PS ASO in a productive tissue compartment. In this report, we measured PS ASO activity following administration by bolus, infusion or co-fusion with EON within hepatocytes and nonparenchymal cells (NPCs), of the liver...
April 27, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28418770/gene-silencing-activity-and-hepatic-accumulation-of-antisense-oligonucleotides-bearing-cholesterol-conjugated-thiono-triester-at-the-gap-region
#5
Mado Nakajima, Takeshi Kasuya, Shinnichi Yokota, Reina Onishi, Tatsuya Ikehara, Akira Kugimiya, Ayahisa Watanabe
Cholesterol (Chol) conjugation to the 5' or 3' end of antisense oligonucleotide (ASO) enables delivery to the liver, and Chol conjugation at the gap region can also be expected to improve delivery to the liver. In this study, we synthesized ASOs bearing the Chol-conjugated thiono triester and evaluated their activity and hepatic accumulation. We found that Chol conjugations at the gap region improved in vitro activity and hepatic accumulation when compared to unconjugated ASOs. However, Chol conjugation with phosphorothioate linkage did not improve in vivo activity in the liver, suggesting the importance of cleaving the phosphodiester between ASO and Chol...
April 18, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28418733/feasibility-of-spect-ct-imaging-to-study-the-pharmacokinetics-of-antisense-oligonucleotides-in-a-mouse-model-of-duchenne-muscular-dystrophy
#6
Evita van de Steeg, Tilman Läppchen, Begoña Aguilera, Harm T Jansen, Daan Muilwijk, Rick Vermue, José W van der Hoorn, Katia Donato, Raffaella Rossin, Peter C de Visser, Maria L H Vlaming
Antisense oligonucleotides (AONs) are promising candidates for treatment of Duchenne muscular dystrophy (DMD), a severe and progressive disease resulting in premature death. However, more knowledge on the pharmacokinetics of new AON drug candidates is desired for effective application in the clinic. We assessed the feasibility of using noninvasive single-photon emission computed tomography-computed tomography (SPECT-CT) imaging to determine AON pharmacokinetics in vivo. To this end, a 2'-O-methyl phosphorothioate AON was radiolabeled with (123)I or (111)In, and administered to mdx mice, a rodent model of DMD...
April 18, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28375679/dual-phase-iontophoresis-for-the-delivery-of-antisense-oligonucleotides
#7
Daniel J Gibson, Sonal S Tuli, Gregory S Schultz
In support of ongoing research in the study of corneal and skin wound healing, we sought to improve on previously published results by using iontophoresis to deliver RNA interference-based oligonucleotides. By using a electromechanics-based approach, we were able to devise a two-phase solution that separated the buffering solution from the antisense oligonucleotide (ASO) solution. The separation was obtained by making the drug solution a higher density than the buffer, leading it to sink directly onto the tissue surface...
April 4, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28437166/virus-like-particles-of-mrna-with-artificial-minimal-coat-proteins-particle-formation-stability-and-transfection-efficiency
#8
Shehrazade Jekhmane, Rob de Haas, Omar Paulino da Silva Filho, Alexander H van Asbeck, Marco Emanuele Favretto, Armando Hernandez Garcia, Roland Brock, Renko de Vries
RNA has enormous potential as a therapeutic, yet, the successful application depends on efficient delivery strategies. In this study, we demonstrate that a designed artificial viral coat protein, which self-assembles with DNA to form rod-shaped virus-like particles (VLPs), also encapsulates and protects mRNA encoding enhanced green fluorescent protein (EGFP) and luciferase, and yields cellular expression of these proteins. The artificial viral coat protein consists of an oligolysine (K12) for binding to the oligonucleotide, a silk protein-like midblock S10 = (GAGAGAGQ)10 that self-assembles into stiff rods, and a long hydrophilic random coil block C that shields the nucleic acid cargo from its environment...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28375678/intracellular-distribution-and-nuclear-activity-of-antisense-oligonucleotides-after-unassisted-uptake-in-myoblasts-and-differentiated-myotubes-in-vitro
#9
Anchel González-Barriga, Bram Nillessen, Julia Kranzen, Ingeborg D G van Kessel, Huib J E Croes, Begoña Aguilera, Peter C de Visser, Nicole A Datson, Susan A M Mulders, Judith C T van Deutekom, Bé Wieringa, Derick G Wansink
Clinical efficacy of antisense oligonucleotides (AONs) for the treatment of neuromuscular disorders depends on efficient cellular uptake and proper intracellular routing to the target. Selection of AONs with highest in vitro efficiencies is usually based on chemical or physical methods for forced cellular delivery. Since these methods largely bypass existing natural mechanisms for membrane passage and intracellular trafficking, spontaneous uptake and distribution of AONs in cells are still poorly understood...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28355131/silencing-of-bcr-abl-chimeric-gene-in-human-chronic-myelogenous-leukemia-cell-line-k562-by-sirna-nuclear-export-signal-peptide-conjugates
#10
Yasuhiro Shinkai, Shinichi Kashihara, Go Minematsu, Hirofumi Fujii, Madoka Naemura, Yojiro Kotake, Yasutaka Morita, Koichiro Ohnuki, Alesya A Fokina, Dmitry A Stetsenko, Vyacheslav V Filichev, Masayuki Fujii
Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28145801/the-effects-of-2-o-methoxyethyl-containing-antisense-oligonucleotides-on-platelets-in-human-clinical-trials
#11
Stanley T Crooke, Brenda F Baker, Joseph L Witztum, T Jesse Kwoh, Nguyen C Pham, Nelson Salgado, Bradley W McEvoy, Wei Cheng, Steven G Hughes, Sanjay Bhanot, Richard S Geary
A thorough analysis of clinical trial data in the Ionis integrated safety database (ISDB) was performed to determine if there is a class effect on platelet numbers and function in subjects treated with 2'-O-methoxyethyl (2'MOE)-modified antisense oligonucleotides (ASOs). The Ionis ISDB includes over 2,600 human subjects treated with 16 different 2'MOE ASOs in placebo-controlled and open-label clinical trials over a range of doses up to 624 mg/week and treatment durations as long as 4.6 years. This analysis showed that there is no class generic effect on platelet numbers and no incidence of confirmed platelet levels below 50 K/μL in subjects treated with 2'MOE ASOs...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28118087/identification-of-a-peptide-for-systemic-brain-delivery-of-a-morpholino-oligonucleotide-in-mouse-models-of-spinal-muscular-atrophy
#12
Fazel Shabanpoor, Suzan M Hammond, Frank Abendroth, Gareth Hazell, Matthew J A Wood, Michael J Gait
Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS)...
June 2017: Nucleic Acid Therapeutics
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
#13
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...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28346110/fda-approval-of-nusinersen-for-spinal-muscular-atrophy-makes-2016-the-year-of-splice-modulating-oligonucleotides
#14
Annemieke Aartsma-Rus
No abstract text is available yet for this article.
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28080221/molecular-mechanisms-of-antisense-oligonucleotides
#15
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...
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051352/antisense-oligonucleotides-targeting-raf-1-block-japanese-encephalitis-virus-in-vitro-and-in-vivo
#16
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...
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051347/-in-house-production-of-single-stranded-oligodeoxyribonucleotides
#17
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...
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28051346/a-conjugate-of-two-tpa-binding-rna-aptamers-efficiently-inhibits-fibrinolysis
#18
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...
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28005462/recognition-of-c9orf72-mutant-rna-by-single-stranded-silencing-rnas
#19
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...
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/27923103/noninvasive-microsurgery-using-aptamer-functionalized-magnetic-microdisks-for-tumor-cell-eradication
#20
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...
April 2017: Nucleic Acid Therapeutics
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