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Antisense oligos

Marina Koutsioumpa, Hsiao-Wang Chen, Neil O'Brien, Filippos Koinis, Swapna Mahurkar-Joshi, Christina Vorvis, Artin Soroosh, Tong Luo, Shawnt Issakhanian, Allan J Pantuck, Vasilis Georgoulias, Dimitrios Iliopoulos, Dennis J Slamon, Alexandra Drakaki
Bladder cancer (BC) represents a disease associated with significant morbidity and mortality. MicroRNA-21 (MiR-21) has been found to have oncogenic activity in multiple cancers, including BC, while inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in BC and evaluate the effects of intravenous (I.V.) and intraperitoneal (I.P.) administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of BC cells, while the MKAD-21 chemically-modified antisense oligo against miR-21, dose-dependently blocked xenograft growth...
April 27, 2018: Molecular Cancer Therapeutics
Hans Gaus, Colton M Miller, Punit P Seth, Edward N Harris
The Stabilin receptors are systemic clearance receptors for some classes of chemically modified nucleic acid therapeutics. In this study, the recombinant human secreted ecto-domain of the small isoform of Stabilin-2 (s190) was purified from cell culture and evaluated for direct binding with a multitude of antisense oligonucleotides (ASOs) using a fluorescence polarization-based assay. The ASOs tested varied in their backbone composition, modification of the ribose 2' position, overall length of the oligo, and sequence of the nucleotide bases...
March 28, 2018: Biochemistry
Shu Meng, Qilin Gu, Xiaojie Yang, Jie Lv, Iris Owusu, Gianfranco Matrone, Kaifu Chen, John P Cooke, Longhou Fang
Background -Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described. Methods -Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo Angiogenesis gene array was used to identify key downstream targets of TBX20...
March 15, 2018: Circulation
Mohamad Moustafa Ali, Vijay Suresh Akhade, Subazini Thankaswamy Kosalai, Santhilal Subhash, Luisa Statello, Matthieu Meryet-Figuiere, Jonas Abrahamsson, Tanmoy Mondal, Chandrasekhar Kanduri
Despite improvement in our understanding of long noncoding RNAs (lncRNAs) role in cancer, efforts to find clinically relevant cancer-associated lncRNAs are still lacking. Here, using nascent RNA capture sequencing, we identify 1145 temporally expressed S-phase-enriched lncRNAs. Among these, 570 lncRNAs show significant differential expression in at least one tumor type across TCGA data sets. Systematic clinical investigation of 14 Pan-Cancer data sets identified 633 independent prognostic markers. Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks...
February 28, 2018: Nature Communications
Linlin Yang, Hyun Bum Kim, Jai-Yoon Sul, Sean B Yeldell, James H Eberwine, Ivan J Dmochowski
Light-activated ("caged") antisense oligonucleotides are powerful molecules for regulating gene expression at submicron spatial resolution through the focal modulation of endogenous cellular processes. Cyclized caged oligos are particularly promising structures because of their inherent stability and similarity to naturally occurring circular DNA and RNA molecules. Here, we introduce an efficient route for cyclizing an antisense oligodeoxynucleotide incorporating a photocleavable linker. Oligo cyclization was achieved for several sequences in nearly quantitative yields through intramolecular copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)...
February 25, 2018: Chembiochem: a European Journal of Chemical Biology
Rashika Joshi, Andrea Heinz, Qiang Fan, Shuling Guo, Brett Monia, Christian E H Schmelzer, Anthony S Weiss, Matthew Batie, Harikrishnan Parameswaran, Brian M Varisco
RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency...
February 8, 2018: American Journal of Respiratory Cell and Molecular Biology
Qinqin Hu, Sheng Wang, Lihua Wang, Hongzhou Gu, Chunhai Fan
In the beginning of the 21st century, therapeutic oligonucleotides have shown great potential for the treatment of many life-threatening diseases. However, effective delivery of therapeutic oligonucleotides to the targeted location in vivo remains a major issue. As an emerging field, DNA nanotechnology is applied in many aspects including bioimaging, biosensing, and drug delivery. With sequence programming and optimization, a series of DNA nanostructures can be precisely engineered with defined size, shape, surface chemistry, and function...
January 22, 2018: Advanced Healthcare Materials
Bao T Le, Abbie M Adams, Susan Fletcher, Stephen D Wilton, Rakesh N Veedu
Locked nucleic acid is a prominent nucleic acid analog with unprecedented target binding affinity to cDNA and RNA oligonucleotides and shows remarkable stability against nuclease degradation. Incorporation of locked nucleic acid nucleotides into an antisense oligonucleotide (AO) sequence can reduce the length required without compromising the efficacy. In this study, we synthesized a series of systematically truncated locked nucleic acid-modified 2'-O-methyl AOs on a phosphorothioate (PS) backbone that were designed to induce skipping exon 23 from the dystrophin transcript in H-2Kb -tsA58 mdx mouse myotubes in vitro...
December 15, 2017: Molecular Therapy. Nucleic Acids
Guo-Feng Liu, Jing-Jing Liu, Zhi-Rong He, Fu-Min Wang, Hua Yang, Yi-Feng Yan, Ming-Jun Gao, Margaret Y Gruber, Xiao-Chun Wan, Shu Wei
Volatile terpenoids produced in tea plants (Camellia sinensis) are airborne signals interacting against other ecosystem members, but also pleasant odorants of tea products. Transcription regulation (including transcript processing) is pivotal for plant volatile terpenoid production. In this study, a terpene synthase gene CsLIS/NES was recovered from tea plants (C. sinensis cv. "Long-Men Xiang"). CsLIS/NES transcription regulation resulted in 2 splicing forms: CsLIS/NES-1 and CsLIS/NES-2 lacking a 305 bp-fragment at N-terminus, both producing (E)-nerolidol and linalool in vitro...
January 2018: Plant, Cell & Environment
Qi-Jie Zhang, Xiang Lin, Jin-Jing Li, Ying-Qian Lu, Xin-Xin Guo, En-Lin Dong, Miao Zhao, Jin He, Ning Wang, Wan-Jin Chen
Spinal muscular atrophy (SMA) is a lethal childhood neurodegenerative disorder that is caused by the homozygous deletion of survival motor neuron 1 (SMN1). To date, no effective treatments are available. In the current study, urine cells taken from SMA patients were cultured and the application of patient-derived urine cells was determined in drug intervention. A total of 13 SMA patient-derived urine cell lines and 40 control cell lines were established. SMN was highly expressed in the nucleus and cytoplasm...
September 2017: Experimental and Therapeutic Medicine
F Berardinelli, E Coluzzi, A Sgura, A Antoccia
One of the hallmarks of cancer consists in the ability of tumor cells to divide indefinitely, and to maintain stable telomere lengths throughout the activation of specific telomere maintenance mechanisms (TMM). Therefore in the last fifteen years, researchers proposed to target telomerase or telomeric structure in order to block limitless replicative potential of cancer cells providing a fascinating strategy for a broad-spectrum cancer therapy. In the present review, we report in vitro and in vivo evidence regarding the use of chemical agents targeting both telomerase or telomere structure and showing promising antitumor effects when used in combination with ionizing radiation (IR)...
July 2017: Mutation Research
Xuechen Zhu, Rui Xing, Renbo Tan, Rongyang Dai, Qinghua Tao
The RING finger protein Rnf146 encodes an E3 ubiquitin ligase capable of targeting poly-ADP-ribosylated substrates for proteasomal degradation. Rnf146 has been identified as a critical regulator of Axin1 and thus of Wnt/β-catenin signaling. However its physiological significance in vertebrate embryonic development remains to be demonstrated. In this study, we take advantages of early Xenopus embryos to demonstrate that Rnf146 is essential for embryonic pattern formation. Depletion of zygotic Rnf146 using a translation blocking morpholino oligo (MO) results in anteriorized development and increased expression the anterior marker gene Otx2, consistent the notion that Rnf146 is a positive regulator of Wnt/β-catenin signaling through negatively regulating Axin1 expression...
October 2017: Mechanisms of Development
Philip A Lewis, Isobel C Bradley, Alastair R Pizzey, Harry V Isaacs, Gareth J O Evans
The presence of the neuronal-specific N1-Src splice variant of the C-Src tyrosine kinase is conserved through vertebrate evolution, suggesting an important role in complex nervous systems. Alternative splicing involving an N1-Src-specific microexon leads to a 5 or 6 aa insertion into the SH3 domain of Src. A prevailing model suggests that N1-Src regulates neuronal differentiation via cytoskeletal dynamics in the growth cone. Here we investigated the role of n1-src in the early development of the amphibian Xenopus tropicalis, and found that n1-src expression is regulated in embryogenesis, with highest levels detected during the phases of primary and secondary neurogenesis...
August 30, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Haruthai Pansuwan, Boonsong Ditmangklo, Chotima Vilaivan, Banphot Jiangchareon, Porntip Pan-In, Supason Wanichwecharungruang, Tanapat Palaga, Thanesuan Nuanyai, Chaturong Suparpprom, Tirayut Vilaivan
Peptide nucleic acid (PNA) is a nucleic acid mimic in which the deoxyribose-phosphate was replaced by a peptide-like backbone. The absence of negative charge in the PNA backbone leads to several unique behaviors including a stronger binding and salt independency of the PNA-DNA duplex stability. However, PNA possesses poor aqueous solubility and cannot directly penetrate cell membranes. These are major obstacles that limit in vivo applications of PNA. In previous strategies, the PNA can be conjugated to macromolecular carriers or modified with positively charged side chains such as guanidinium groups to improve the aqueous solubility and cell permeability...
September 20, 2017: Bioconjugate Chemistry
Duo Zhang, Heedoo Lee, Jeffrey A Haspel, Yang Jin
The function of most human long noncoding RNAs (lncRNAs) remains unclear. Our studies identified a highly up-regulated mammalian lncRNA, FOXD3-AS1 , known as linc1623 in mice, in the setting of hyperoxia/reactive oxygen species (ROS)-induced lung injury. We found that ROS induced a robust expression of FOXD3 -AS1 in mouse lung tissue. Functionally, FOXD3-AS1 promoted oxidative stress-induced lung epithelial cell death. In human lung epithelial cells, the microRNA-150 (miR-150) was identified to interact with FOXD3-AS1 ; this finding was confirmed using the luciferase reporter assays...
October 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Oleksandr Plashkevych, Ram Shankar Upadhayaya, Jyoti Chattopadhyaya
In light of the impressive gene-silencing properties of carba-LNA modified oligo DNA and RNA, both in antisense RNA and siRNA approaches, which have been confirmed as proof-of-concept for biochemical applications in post-transcriptional gene silencing, we envision the true potential of carba-LNA modifications to be revealed soon. Herein we provide detailed protocols for synthesis of carba-LNA-A, -G, -(5-Me) C, and -T nucleosides on a medium/large scale (gram scale), as well as important guidelines for incorporation of these modified carba-LNAs into DNA or RNA oligonucleotides...
June 19, 2017: Current Protocols in Nucleic Acid Chemistry
Guo-Lin Chen, Qi Ma, Dharmendra Goswami, Jianyu Shang, Gregory M Miller
Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting...
November 2017: Journal of Cellular and Molecular Medicine
Cy A Stein, Daniela Castanotto
Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and followed about 15 years ago by siRNAs. During that lengthy period of time, numerous clinical trials have been performed and thousands of trial participants accrued onto studies. Of all the molecules evaluated as of January 2017, the regulatory authorities assessed that six provided clear clinical benefit in rigorously controlled trials. The story of these six is given in this review...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
James E Summerton
Beginning with my concept in 1969 to treat disease at the nucleic acid level using antisense nucleic acids, antisense has evolved to the current Morpholino oligos. Morpholinos have been the dominant gene knockdown system in developmental biology. Lack of delivery technologies has limited their use in adult animals (including humans), though alteration in muscles in Duchenne muscular dystrophy (DMD) allows delivery into adult muscle. Morpholinos are currently in Phase 3 clinical trials for DMD and a Morpholino oligo for skipping dystrophin exon 51 has been approved by the US FDA...
2017: Methods in Molecular Biology
Chiara De Santi, Sebastian Vencken, Jonathon Blake, Bettina Haase, Vladimir Benes, Federica Gemignani, Stefano Landi, Catherine M Greene
MicroRNAs (miRNAs) are small non-coding RNAs that regulate mRNA expression mainly by silencing target transcripts via binding to miRNA recognition elements (MREs) in the 3'untranslated region (3'UTR). The identification of bona fide targets is challenging for researchers working on the functional aspect of miRNAs. Recently, we developed a method (miR-CATCH) based on biotinylated DNA antisense oligonucleotides that capture the mRNA of interest and facilitates the characterisation of miRNAs::mRNA interactions in a physiological cellular context...
2017: PloS One
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