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Antisense oligonucleotide

Detlef Schuppan, Muhammad Ashfaq-Khan, Ai Ting Yang, Yong Ook Kim
Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases...
April 12, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Margaux Sevin, Lucia Kubovcakova, Nicolas Pernet, Sébastien Causse, Franck Vitte, Jean Luc Villeval, Catherine Lacout, Marine Cordonnier, Fernando Rodrigues-Lima, Gaétan Chanteloup, Matthieu Mosca, Marie-Lorraine Chrétien, Jean Noël Bastie, Sylvain Audia, Paul Sagot, Selim Ramla, Laurent Martin, Martin Gleave, Valérie Mezger, Radek Skoda, Isabelle Plo, Carmen Garrido, François Girodon, Aurélie de Thonel
Heat shock protein 27 (HSP27/HSPB1) is a stress-inducible chaperone that facilitates cancer development by its proliferative and anti-apoptotic functions. The OGX-427 antisense oligonucleotide against HSP27 has been reported to be beneficial against idiopathic pulmonary fibrosis. Here we show that OGX-427 is effective in two murine models of thrombopoietin- and JAKV617F-induced myelofibrosis. OGX-427 limits disease progression and is associated with a reduction in spleen weight, in megakaryocyte expansion and, for the JAKV617F model, in fibrosis...
April 12, 2018: Nature Communications
Kensuke Toyama, Joshua M Spin, Alicia C Deng, Ting-Ting Huang, Ke Wei, Markus U Wagenhäuser, Takuya Yoshino, Huy Nguyen, Joscha Mulorz, Soumajit Kundu, Uwe Raaz, Matti Adam, Isabel N Schellinger, Ann Jagger, Philip S Tsao
OBJECTIVE: There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood-brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood-brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment...
April 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Joseph Aizen, Yefei Pang, Caleb Harris, Aubrey Converse, Yong Zhu, Meagan A Aguirre, Peter Thomas
Although previous studies suggest membrane progesterone receptor alpha (mPRα/Paqr7) mediates 17, 20β-dihydroxy-4-pregnen-3-one (DHP) induction of oocyte maturation (OM) in zebrafish, critical information needed to establish mPRα as the receptor mediating OM, is lacking. The relative potencies of progestins and specific mPRα agonists in inducing OM matched their relative binding affinities for zebrafish mPRα, supporting its role in OM. Microinjection of pertussis toxin blocked DHP induction of OM and the progestin-induced decrease in cyclic AMP levels, suggesting mPRα activates an inhibitory G protein (Gi)...
April 9, 2018: General and Comparative Endocrinology
Michael K K Leung, Andrew Delong, Brendan J Frey
Motivation: Processing of transcripts at the 3'-end involves cleavage at a polyadenylation site followed by the addition of a poly(A)-tail. By selecting which site is cleaved, the process of alternative polyadenylation enables genes to produce transcript isoforms with different 3'-ends. To facilitate the identification and treatment of disease-causing mutations that affect polyadenylation and to understand the sequence determinants underlying this regulatory process, a computational model that can accurately predict polyadenylation patterns from genomic features is desirable...
April 10, 2018: Bioinformatics
Shohei Mori, Kunihiko Morihiro, Takumi Okuda, Yuuya Kasahara, Satoshi Obika
Hydrogen peroxide (H2 O2 ) is a reactive oxygen species (ROS) involved in various diseases, including neurodegeneration, diabetes, and cancer. Here, we introduce a new approach to use H2 O2 to modulate specific gene expression in mammalian cells. H2 O2 -responsive nucleoside analogues, in which the Watson-Crick faces of the nucleobases are caged by arylboronate moieties, were synthesized. One of these analogues, boronated thymidine ( dTB ), was incorporated into oligodeoxynucleotides (ODNs) using an automated DNA synthesizer...
February 7, 2018: Chemical Science
Jennifer L Chang, Anthony J Hinrich, Brandon Roman, Michaela Norrbom, Frank Rigo, Robert A Marr, Eric M Norstrom, Michelle L Hastings
Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Maria Domenica Sanna, Alessandro Quattrone, Nicoletta Galeotti
Currently available antidepressant drugs often fail to achieve full remission and patients might evolve to treatment resistance, showing the need to achieve a better therapy of depressive disorders. Increasing evidence supports that post-transcriptional regulation of gene expression is important in neuronal development and survival and a relevant role is played by RNA binding proteins (RBP). To explore new therapeutic strategies, we investigated the role of the neuron-specific ELAV-like RBP (HuB, HuC, HuD) in a mouse model of depression...
April 4, 2018: Neuropharmacology
Willeke M C van Roon-Mom, Raymund A C Roos, Susanne T de Bot
On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data...
April 2018: Nucleic Acid Therapeutics
Xiaoye Su, Ruiting Liang, Jessica A Stolee
Oligonucleotides are being researched and developed as potential drug candidates for the treatment of a broad spectrum of diseases. The characterization of antisense oligonucleotide (ASO) impurities caused by base mutations (e.g. deamination) which are closely related to the target ASO is a significant analytical challenge. Herein, we describe a novel one-step method, utilizing a strategy that combines fluorescence-ON detection with competitive hybridization, to achieve single base mutation quantitation in extensively modified synthetic ASOs...
March 27, 2018: Journal of Pharmaceutical and Biomedical Analysis
Kota Kamizato, Silvia Marsala, Michael Navarro, Manabu Kakinohana, Oleksandr Platoshyn, Tetsuya Yoshizumi, Nadezda Lukacova, Ed Wancewicz, Berit Powers, Curt Mazur, Martin Marsala
The loss of local spinal glycine-ergic tone has been postulated as one of the mechanisms contributing to the development of spinal injury-induced spasticity. In our present study using a model of spinal transection-induced muscle spasticity, we characterize the effect of spinally-targeted GlyT2 downregulation once initiated at chronic stages after induction of spasticity in rats. In animals with identified hyper-reflexia, the anti-spasticity effect was studied after intrathecal treatment with: i) glycine, ii) GlyT2 inhibitor (ALX 1393), and iii) GlyT2 antisense oligonucleotide (GlyT2-ASO)...
March 30, 2018: Experimental Neurology
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
Xianli Bian, Pengfei Lin, Jiangxia Li, Feng Long, Ruonan Duan, Qianqian Yuan, Yan Li, Fei Gao, Shang Gao, Shijun Wei, Xi Li, Wenjie Sun, Yaoqin Gong, Chuanzhu Yan, Qiji Liu
BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common neurodegenerative disorder of the peripheral nervous system. More than 50 genes/loci were found associated with the disease. We found a family with autosomal-dominant CMT2. OBJECTIVE: To reveal the pathogenic gene of the family and further investigate the function of the variant. METHODS: DNA underwent whole-genome linkage analysis for all family members and whole-exome sequencing for 2 affected members...
March 27, 2018: Neuro-degenerative Diseases
Hui Gao, Alastair Kerr, Hong Jiao, Chung-Chau Hon, Mikael Rydén, Ingrid Dahlman, Peter Arner
Long non-coding RNAs (lncRNAs) belong to a recently discovered class of molecules proposed to regulate various cellular processes. Here, we systematically analyzed their expression in human subcutaneous white adipose tissue (WAT) and found that a limited set was differentially expressed in obesity and/or the insulin resistant state. Two lncRNAs herein termed adipocyte-specific metabolic related lncRNAs, ASMER-1 and ASMER-2 were enriched in adipocytes and regulated by both obesity and insulin resistance. Knockdown of either ASMER-1 or ASMER-2 by antisense oligonucleotides in in vitro differentiated human adipocytes revealed that both genes regulated adipogenesis, lipid mobilization and adiponectin secretion...
March 15, 2018: EBioMedicine
Lingyun Zhu, Junlong Bi, Longlong Zheng, Qian Zhao, Xianghua Shu, Gang Guo, Jia Liu, Guishu Yang, Jianping Liu, Gefen Yin
BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) causes porcine reproductive and respiratory syndrome (PRRS), which is currently insufficiently controlled. From a previous small-scale screen we identified an effective DNA-based short antisense oligonucleotide (AS-ON) targeting viral NSP9, which could inhibit PRRSV replication in both Marc-145 cells and pulmonary alveolar macrophages (PAMs). The objective of this study was to explore the strategy of incorporating locked nucleic acids (LNAs) to achieve better inhibition of PRRSV replication in vitro...
March 26, 2018: BMC Veterinary Research
Valentina Sardone, Matthew Ellis, Silvia Torelli, Lucy Feng, Darren Chambers, Deborah Eastwood, Caroline Sewry, Rahul Phadke, Jennifer E Morgan, Francesco Muntoni
Clinical trials using strategies aimed at inducing dystrophin expression in Duchenne muscular dystrophy (DMD) are underway or at advanced planning stage, including splice switching antisense oligonucleotides (AON), drugs to induce read-through of nonsense mutations and viral mediated gene therapy. In all these strategies, different dystrophin proteins, often internally deleted, are produced, similar to those found in patients with the milder DMD allelic variant, Becker muscular dystrophy (BMD). The primary biological endpoint of these trials is to induce functional dystrophin expression...
2018: PloS One
Jingshu Chen, Sui Ke, Lei Zhong, Jing Wu, Alexander Tseng, Benjamin Morpurgo, Andrei Golovko, Gang Wang, James J Cai, Xi Ma, Defa Li, Yanan Tian
The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA and its overexpression is associated with the development of many types of malignancy. MALAT1 null mice show no overt phenotype. However, in transcriptome analysis of MALAT1 null mice we found significant upregulation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulated antioxidant genes including Nqo1 and Cat with significant reduction in reactive oxygen species (ROS) and greatly reduced ROS-generated protein carbonylation in hepatocyte and islets...
March 22, 2018: Biochemical Pharmacology
Nicholas J Viney, Calvin Yeang, Xiaohong Yang, Shuting Xia, Joseph L Witztum, Sotirios Tsimikas
BACKGROUND: The laboratory measurement of "low-density lipoprotein cholesterol (LDL-C)" includes the cholesterol content of lipoprotein(a) (Lp(a)-C). OBJECTIVE: To estimate the "true" LDL-C in relation to changes in apolipoprotein B-100 (apoB-100) and assess changes in proprotein convertase subtilisin/kexin 9 (PCSK9) levels in patients with elevated Lp(a) treated with IONIS-APO(a)Rx. METHODS: A pooled placebo group (n = 29), and cohort A (n = 24, baseline Lp(a) 50-175 mg/dL) and cohort B (n = 8, baseline Lp(a) > 175 mg/dL) treated with IONIS-APO(a)Rx were studied...
March 1, 2018: Journal of Clinical Lipidology
James S Novak, Marshall W Hogarth, Jessica F Boehler, Marie Nearing, Maria C Vila, Raul Heredia, Alyson A Fiorillo, Aiping Zhang, Yetrib Hathout, Eric P Hoffman, Jyoti K Jaiswal, Kanneboyina Nagaraju, Sebahattin Cirak, Terence A Partridge
The originally published version of this Article contained an error in Figure 6. In panel b, the top graph (BrdU 21-24d) and the bottom graph (BrdU 28-31d) were inadvertently swapped. This error has now been corrected in both the PDF and HTML versions of the Article.
March 23, 2018: Nature Communications
Sanjay Awasthi, Joshua Tompkins, Jyotsana Singhal, Arthur D Riggs, Sushma Yadav, Xiwei Wu, Sharda Singh, Charles Warden, Zheng Liu, Jinhui Wang, Thomas P Slavin, Jeffrey N Weitzel, Yate-Ching Yuan, Meenakshi Awasthi, Satish K Srivastava, Yogesh C Awasthi, Sharad S Singhal
TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53-/- ) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53-/- mice, Rlip-/- mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo( a )pyrene-induced carcinogenesis in p53-/- mice...
March 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
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