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Antisense oligonucleotide

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https://www.readbyqxmd.com/read/28325303/inhibition-of-egf-uptake-by-nephrotoxic-antisense-drugs-in%C3%A2-vitro-and-implications-for-preclinical-safety-profiling
#1
Annie Moisan, Marcel Gubler, Jitao David Zhang, Yann Tessier, Kamille Dumong Erichsen, Sabine Sewing, Régine Gérard, Blandine Avignon, Sylwia Huber, Fethallah Benmansour, Xing Chen, Roberto Villaseñor, Annamaria Braendli-Baiocco, Matthias Festag, Andreas Maunz, Thomas Singer, Franz Schuler, Adrian B Roth
Antisense oligonucleotide (AON) therapeutics offer new avenues to pursue clinically relevant targets inaccessible with other technologies. Advances in improving AON affinity and stability by incorporation of high affinity nucleotides, such as locked nucleic acids (LNA), have sometimes been stifled by safety liabilities related to their accumulation in the kidney tubule. In an attempt to predict and understand the mechanisms of LNA-AON-induced renal tubular toxicity, we established human cell models that recapitulate in vivo behavior of pre-clinically and clinically unfavorable LNA-AON drug candidates...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28302155/a-prospective-randomised-placebo-controlled-double-masked-three-armed-multicentre-phase-ii-iii-trial-for-the-study-of-a-topical-treatment-of-ischaemic-central-retinal-vein-occlusion-to-prevent-neovascular-glaucoma-the-strong-study-study-protocol-for-a-randomised
#2
Katrin Lorenz, Yvonne Scheller, Katharina Bell, Franz Grus, Katharina A Ponto, Felix Bock, Claus Cursiefen, Jens Flach, Marta Gehring, Tunde Peto, Rufino Silva, Yossi Tal, Norbert Pfeiffer
BACKGROUND: Neovascular glaucoma (NVG) is rare, comprising only 3.9% of all glaucoma cases. The most common cause of NVG is ischaemic central retinal vein occlusion (iCRVO). NVG frequently results in blindness and painful end-stage glaucomatous damage leading to the need for enucleation. Currently, there is no preventive therapy for NVG following iCRVO. Rescue treatments have severe drawbacks. Accordingly, there is a great need for preventing the often visually devastating outcomes of NVG...
March 16, 2017: Trials
https://www.readbyqxmd.com/read/28300830/smad7-knockdown-activates-protein-kinase-rna-associated-eif2%C3%AE-pathway-leading-to-colon-cancer-cell-death
#3
Veronica De Simone, Gerolamo Bevivino, Silvia Sedda, Roberta Izzo, Federica Laudisi, Vincenzo Dinallo, Eleonora Franzè, Alfredo Colantoni, Angela Ortenzi, Silvia Salvatori, Piero Rossi, Giuseppe S Sica, Massimo C Fantini, Carmine Stolfi, Giovanni Monteleone
Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2α...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28294391/a-population-pharmacokinetic-meta-analysis-of-custirsen-an-antisense-oligonucleotide-in-oncology-patients-and-healthy-subjects
#4
Alena Y Edwards, Anna Elgart, Colm Farrell, Ofra Barnett-Griness, Laura Rabinovich-Guilatt, Ofer Spiegelstein
AIMS: Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide that reduces clusterin production, is under investigation with chemotherapy in prostate and lung cancer. This meta-analysis evaluated the population pharmacokinetics (PK) of custirsen in cancer patients and healthy subjects. METHODS: The population PK analysis used custirsen plasma concentrations from five phase 1 studies, one phase 1/2 study, and one phase 3 study in two stages. Cancer patients received multiple doses of custirsen (40-640 mg intravenously over 120 minutes) with chemotherapy; healthy subjects received single or multiple doses (320-640 mg)...
March 11, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28292178/antisense-oligonucleotides-internally-labeled-with-peptides-show-improved-target-recognition-and-stability-to-enzymatic-degradation
#5
Maria Taskova, Charlotte S Madsen, Knud J Jensen, Lykke Haastrup Hansen, Birte Vester, Kira Astakhova
Specific target binding and stability in diverse biological media is of crucial importance for applications of synthetic oligonucleotides as diagnostic and therapeutic tools. So far, these issues have been addressed by chemical modification of oligonucleotides and by conjugation with a peptide, most often at the terminal position of the oligonucleotide. Herein, we for the first time systematically investigate the influence of internally attached short peptides on the properties of antisense oligonucleotides...
March 15, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28289706/plastin-3-extends-survival-and-reduces-severity-in-mouse-models-of-spinal-muscular-atrophy
#6
Kevin A Kaifer, Eric Villalón, Erkan Y Osman, Jacqueline J Glascock, Laura L Arnold, D D W Cornelison, Christian L Lorson
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289078/delivery-is-key-lessons-learnt-from-developing-splice-switching-antisense-therapies
#7
REVIEW
Caroline Godfrey, Lourdes R Desviat, Bård Smedsrød, France Piétri-Rouxel, Michela A Denti, Petra Disterer, Stéphanie Lorain, Gisela Nogales-Gadea, Valentina Sardone, Rayan Anwar, Samir El Andaloussi, Taavi Lehto, Bernard Khoo, Camilla Brolin, Willeke Mc van Roon-Mom, Aurélie Goyenvalle, Annemieke Aartsma-Rus, Virginia Arechavala-Gomeza
The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre-clinical development, the gaps in current knowledge and the pertinent challenges facing the field...
March 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28288210/depletion-of-neat1-lncrna-attenuates-nucleolar-stress-by-releasing-sequestered-p54nrb-and-psf-to-facilitate-c-myc-translation
#8
Wen Shen, Xue-Hai Liang, Hong Sun, Cheryl L De Hoyos, Stanley T Crooke
Altered expression of NEAT1, the architectural long non-coding RNA (lncRNA) of nuclear paraspeckles, has been reported during tumorigenesis, as well as under various cellular stress conditions. Here we report that the depletion of NEAT1 lncRNA alleviates nucleolar stress during RNAP I inhibition through releasing sequestered P54nrb and PSF to facilitate the IRES-dependent translation of c-Myc. RNAP I inhibitor CX5461 disrupts the SL1-rDNA interaction and induces nucleolar disruption, demonstrated by the accumulation of fibrillarin-containing nucleoplasmic foci and nucleolar clearance of ribosomal proteins in HeLa cells...
2017: PloS One
https://www.readbyqxmd.com/read/28286423/oligonucleotides-targeting-coagulation-factor-mrnas-use-in-thrombosis-and-hemophilia-research-and-therapy
#9
REVIEW
Marco Heestermans, Bart J M van Vlijmen
Small interfering (si) RNAs and antisense oligonucleotides (ASOs; here for simplicity reasons, both referred to as oligonucleotides) are small synthetic RNA or DNA molecules with a sequence complementary to a (pre)mRNA. Although the basic mechanisms of action between siRNAs and ASO are distinct, a sequence-specific interaction of the both oligonucleotides with the target (pre)mRNA alters the target's fate, which includes highly effective sequence-specific blockade of translation and consequently depletion of the corresponding protein...
2017: Thrombosis Journal
https://www.readbyqxmd.com/read/28283282/custirsen-in-combination-with-docetaxel-and-prednisone-for-patients-with-metastatic-castration-resistant-prostate-cancer-synergy-trial-a-phase-3-multicentre-open-label-randomised-trial
#10
Kim N Chi, Celestia S Higano, Brent Blumenstein, Jean-Marc Ferrero, James Reeves, Susan Feyerabend, Gwenaelle Gravis, Axel S Merseburger, Arnulf Stenzl, Andries M Bergman, Som D Mukherjee, Pawel Zalewski, Fred Saad, Cindy Jacobs, Martin Gleave, Johann S de Bono
BACKGROUND: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. METHODS: SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries...
March 7, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28281657/a-gcsfr-csf3r-zebrafish-mutant-models-the-persistent-basal-neutrophil-deficiency-of-severe-congenital-neutropenia
#11
Vahid Pazhakh, Sharon Clark, M Cristina Keightley, Graham J Lieschke
Granulocyte colony-stimulating factor (GCSF) and its receptor (GCSFR), also known as CSF3 and CSF3R, are required to maintain normal neutrophil numbers during basal and emergency granulopoiesis in humans, mice and zebrafish. Previous studies identified two zebrafish CSF3 ligands and a single CSF3 receptor. Transient antisense morpholino oligonucleotide knockdown of both these ligands and receptor reduces neutrophil numbers in zebrafish embryos, a technique widely used to evaluate neutrophil contributions to models of infection, inflammation and regeneration...
March 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28278199/monitoring-integrity-and-localization-of-modified-single-stranded-rna-oligonucleotides-using-ultrasensitive-fluorescence-methods
#12
Philipp Heissig, Waldemar Schrimpf, Philipp Hadwiger, Ernst Wagner, Don C Lamb
Short single-stranded oligonucleotides represent a class of promising therapeutics with diverse application areas. Antisense oligonucleotides, for example, can interfere with various processes involved in mRNA processing through complementary base pairing. Also RNA interference can be regulated by antagomirs, single-stranded siRNA and single-stranded microRNA mimics. The increased susceptibility to nucleolytic degradation of unpaired RNAs can be counteracted by chemical modification of the sugar phosphate backbone...
2017: PloS One
https://www.readbyqxmd.com/read/28277980/sidt2-mediates-gymnosis-the-uptake-of-naked-single-stranded-oligonucleotides-into-living-cells
#13
Masayuki Takahashi, Viorica Raluca Contu, Chihana Kabuta, Katsunori Hase, Yuuki Fujiwara, Keiji Wada, Tomohiro Kabuta
Single-stranded oligonucleotides (ssOligos) are efficiently taken up by living cells without the use of transfection reagents. This phenomenon called 'gymnosis' enables the sequence-specific silencing of target genes in various types of cells. Several antisense ssOligos are used for the treatment of human diseases. However, the molecular mechanism underlying the uptake of naked ssOligos into cells remains to be elucidated. Here, we show that systemic RNA interference deficient-1 (SID-1) transmembrane family 2 (SIDT2), a mammalian ortholog of the Caenorhabditis elegans double-stranded RNA channel SID-1, mediates gymnosis...
March 9, 2017: RNA Biology
https://www.readbyqxmd.com/read/28274742/a-hyaluronic-acid-based-hydrogel-enabling-cd44-mediated-chondrocyte-binding-and-gapmer-oligonucleotide-release-for-modulation-of-gene-expression-in-osteoarthritis
#14
Yunpeng Cai, Elena López-Ruiz, Jesper Wengel, Laura B Creemers, Kenneth A Howard
Hyaluronic acid (HA) is an attractive biomaterial for osteoarthritis (OA) treatment due to inherent functional and compatibility properties as an endogenous knee joint component. In this work, we describe a HA-based hydrogel with the dual functionality of increased CD44-dependent chondrocyte binding and controlled release of gapmer antisense oligonucleotides for unassisted cellular entry and subsequent gene silencing activity. A Schiff base-mediated gelation method was used to produce a panel of hydrogels varying in the aldehyde-modified HA (900kDa) to chitosan ratios (3:7, 5:5 and 7:3) for identifying designs displaying optimal engagement of OA patient-derived CD44-expressing chondrocytes...
March 5, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28273791/antisense-oligonucleotides-used-to-target-the-dux4-mrna-as-therapeutic-approaches-in-faciosscapulohumeral-muscular-dystrophy-fshd
#15
Eugénie Ansseau, Céline Vanderplanck, Armelle Wauters, Scott Q Harper, Frédérique Coppée, Alexandra Belayew
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription...
March 3, 2017: Genes
https://www.readbyqxmd.com/read/28271991/new-therapy-for-spinal-muscular-atrophy-offers-modest-bang-for-pharamaceutical-buck
#16
Thomas Morrow
Spinraza is a breakthrough, no doubt. It is a survival SMN-2-directed antisense oligonucleotide indicated for the treatment of SMA in pediatric and adult patients and is administered by injections into the spinal fluid (intrathecally). But it is another ultraexpensive drug, and the evidence so far points to a modest improvement in motor milestones.
February 2017: Managed Care
https://www.readbyqxmd.com/read/28270613/smn-deficiency-in-severe-models-of-spinal-muscular-atrophy-causes-widespread-intron-retention-and-dna-damage
#17
Mohini Jangi, Christina Fleet, Patrick Cullen, Shipra V Gupta, Shila Mekhoubad, Eric Chiao, Norm Allaire, C Frank Bennett, Frank Rigo, Adrian R Krainer, Jessica A Hurt, John P Carulli, John F Staropoli
Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28266272/multiscale-molecular-simulations-applied-to-nucleic-acid-dendrimer-interactions-studies
#18
Fernando Danilo González-Nilo, Ingrid Araya-Durán, Valeria Márquez-Miranda
BACKGROUND: Dendrimers are monodisperse, regular, three-dimensional and small-scale macromolecules that can be used to release substances such as drugs, markers, and genetic material into the cells. Among these substances, nucleic acids such as plasmid DNA, antisense oligonucleotides (asODN), and small-interfering RNA (siRNA) are widely used as therapeutic macromolecules for the treatment and prevention of diverse diseases. Several studies were focused on the modification of dendrimers aiming to improve their affinity for nucleic acids and their ability to release nucleic acids inside the cells...
March 5, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28264911/androgen-receptor-in-cancer-associated-fibroblasts-influences-stemness-in-cancer-cells
#19
Chun-Peng Liao, Leng-Ying Chen, Andrea Luethy, Youngsoo Kim, Kian Kani, A Robert MacLeod, Mitchell E Gross
Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten(-/-)L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells...
April 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28260089/overexpression-of-mir%C3%A2-214-promotes-the-progression-of-human-osteosarcoma-by-regulating-the-wnt-%C3%AE-%C3%A2-catenin-signaling-pathway
#20
Xun-Bing Zhu, Zhong-Chuan Zhang, Guan-Sheng Han, Jun-Zhu Han, Da-Peng Qiu
The aberrant expression of microRNA (miR)‑214 contributes to the regulation of normal and cancer cell biology, and is associated with human malignancies, however, it can operate in a contradictory manner. The role of miR‑214 in osteosarcoma remains to be fully elucidated. The aim of the present study was to investigate the effects of miR‑214 on osteosarcoma progression and tumor cell proliferation, and examine the molecular mechanism underlying osteosarcoma. The level of miR‑214 was determined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis in osteosarcoma and matched paracancerous tissues, and in human osteosarcoma cancer cell lines...
February 14, 2017: Molecular Medicine Reports
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