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Antisense oligonucleotide

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https://www.readbyqxmd.com/read/29230365/identification-and-characterization-of-a-novel-zebrafish-danio-rerio-pentraxin-carbonic-anhydrase
#1
Maarit S Patrikainen, Martti E E Tolvanen, Ashok Aspatwar, Harlan R Barker, Csaba Ortutay, Janne Jänis, Mikko Laitaoja, Vesa P Hytönen, Latifeh Azizi, Prajwol Manandhar, Edit Jáger, Daniela Vullo, Sampo Kukkurainen, Mika Hilvo, Claudiu T Supuran, Seppo Parkkila
Background: Carbonic anhydrases (CAs) are ubiquitous, essential enzymes which catalyze the conversion of carbon dioxide and water to bicarbonate and H+ ions. Vertebrate genomes generally contain gene loci for 15-21 different CA isoforms, three of which are enzymatically inactive. CA VI is the only secretory protein of the enzymatically active isoforms. We discovered that non-mammalian CA VI contains a C-terminal pentraxin (PTX) domain, a novel combination for both CAs and PTXs. Methods: We isolated and sequenced zebrafish (Danio rerio) CA VI cDNA, complete with the sequence coding for the PTX domain, and produced the recombinant CA VI-PTX protein...
2017: PeerJ
https://www.readbyqxmd.com/read/29226998/antisense-suppression-of-glial-fibrillary-acidic-protein-as-a-treatment-for-alexander-disease
#2
Tracy L Hagemann, Berit Powers, Curt Mazur, Aneeza Kim, Steven Wheeler, Gene Hung, Eric Swayze, Albee Messing
OBJECTIVE: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is over-expression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease...
December 11, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29223139/novel-treatments-for-inflammatory-bowel-disease
#3
Hyo Sun Lee, Soo-Kyung Park, Dong Il Park
Increased understanding of the immunopathology of inflammatory bowel disease (IBD) has led to the development of targeted therapies and has unlocked a new era in IBD treatment. The development of treatment options aimed at a variety of pathological mechanisms offers new hope for customized therapies. Beyond anti-tumor necrosis factor agents, selective lymphocyte trafficking inhibitors have been proposed as potent drugs for IBD. Among these, vedolizumab has recently been approved for both Crohn's disease and ulcerative colitis...
December 11, 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/29220503/downregulation-of-survivin-contributes-to-cell-cycle-arrest-during-postnatal-cardiac-development-in-a-severe-spinal-muscular-atrophy-mouse-model
#4
Lei Sheng, Bo Wan, Pengchao Feng, Junjie Sun, Frank Rigo, C Frank Bennett, Martin Akerman, Adrian R Krainer, Yimin Hua
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive degeneration of spinal-cord motor neurons, leading to atrophy of skeletal muscles. However, accumulating evidence indicates that it is a multi-system disorder, particularly in its severe forms. Several studies delineated structural and functional cardiac abnormalities in SMA patients and mouse models, yet the abnormalities have been primarily attributed to autonomic dysfunction. Here, we show in a severe mouse model that its cardiomyocytes undergo G0/G1 cell-cycle arrest and enhanced apoptosis during postnatal development...
December 6, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29218782/therapy-development-in-huntington-disease-from-current-strategies-to-emerging-opportunities
#5
REVIEW
Audrey S Dickey, Albert R La Spada
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration...
December 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29216448/age-dependent-effects-of-apoe-reduction-using-antisense-oligonucleotides-in-a-model-of-%C3%AE-amyloidosis
#6
Tien-Phat V Huynh, Fan Liao, Caroline M Francis, Grace O Robinson, Javier Remolina Serrano, Hong Jiang, Joseph Roh, Mary Beth Finn, Patrick M Sullivan, Thomas J Esparza, Floy R Stewart, Thomas E Mahan, Jason D Ulrich, Tracy Cole, David M Holtzman
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months...
December 6, 2017: Neuron
https://www.readbyqxmd.com/read/29212210/mir-21-silencing-ameliorates-experimental-autoimmune-encephalomyelitis-by-promoting-the-differentiation-of-il-10-producing-b-cells
#7
Hui Wang, Wenrong Xu, Qixiang Shao, Qing Ding
IL-10-producing regulatory B (IL-10+ Breg) cells promote tolerance in autoimmune diseases and transplantation. However, it remains unclear whether microRNAs are involved in the development of IL-10+ Breg cells. Here, we found that microRNA-21 (miR-21) acts as an upstream regulator of IL-10 by targeting the 3' untranslated region of IL-10 mRNA. We also demonstrated that IL-10+ Breg cells exhibit lower miR-21 expression than non-Breg cells and that miR-21 acts as a potent negative regulator of the differentiation of IL-10+ Breg cells...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29209794/advances-in-therapeutic-bacterial-antisense-biotechnology
#8
REVIEW
John P Hegarty, David B Stewart
Antisense therapeutics are a biotechnological form of antibiotic therapy using chemical analogues of short single-stranded nucleic acid sequences modified to form stable oligomers. These molecules are termed antisense oligonucleotides (ASOs) because their sequence is complementary, via Watson-Crick specific base pairing, to their target messenger RNA (mRNA). ASOs modify gene expression in this sequence-dependent manner by binding to its complementary mRNA and inhibiting its translation into protein through steric blockage and/or through RNase degradation of the ASO/RNA duplex...
December 5, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29209494/rnai-mechanisms-in-huntington-s-disease-therapy-sirna-versus-shrna
#9
REVIEW
Sebastian Aguiar, Bram van der Gaag, Francesco Albert Bosco Cortese
Huntington's Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (> 36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT)...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29207381/alicaforsen-an-antisense-inhibitor-of-intercellular-adhesion-molecule-1-in-the-treatment-for-left-sided-ulcerative-colitis-and-ulcerative-proctitis
#10
Thomas Greuter, Stephan R Vavricka, Luc Biedermann, Julia Pilz, Jan Borovicka, Frank Seibold, Bernhard Sauter, Gerhard Rogler
BACKGROUND: Data on the efficacy of intercellular adhesion molecule-1 antisense oligonucleotide alicaforsen in ulcerative colitis (UC) is inconsistent. METHODS: All patients, who had received at least one dose of alicaforsen, were analyzed retrospectively. Alicaforsen's efficacy was assessed in patients treated for left-sided UC and proctitis by comparing clinical and (if applicable) endoscopic disease activity before/after treatment. RESULTS: Twelve patients were treated for left-sided UC or proctitis...
December 5, 2017: Digestive Diseases
https://www.readbyqxmd.com/read/29203355/a-randomized-placebo-controlled-phase-3-trial-of-an-antisense-oligonucleotide-drisapersen-in-duchenne-muscular-dystrophy
#11
Nathalie Goemans, Eugenio Mercuri, Elena Belousova, Hirofumi Komaki, Alberto Dubrovsky, Craig M McDonald, John E Kraus, Afrodite Lourbakos, Zhengning Lin, Giles Campion, Susanne X Wang, Craig Campbell
This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10...
December 1, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29202483/pmp22-antisense-oligonucleotides-reverse-charcot-marie-tooth-disease-type-1a-features-in-rodent-models
#12
Hien Tran Zhao, Sagar Damle, Karli Ikeda-Lee, Steven Kuntz, Jian Li, Apoorva Mohan, Aneeza Kim, Gene Hung, Mark A Scheideler, Steven S Scherer, John Svaren, Eric E Swayze, Holly B Kordasiewicz
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models...
December 4, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29200659/electrochemical-detection-of-urinary-micrornas-via-sulfonamide-bound-antisense-hybridisation
#13
Daniel A Smith, Lucy J Newbury, Guido Drago, Timothy Bowen, James E Redman
Altered serum and plasma microRNA (miRNA) expression profiles have been observed in numerous human diseases, with a number of studies describing circulating miRNA biomarkers for cancer diagnosis, prognosis and response to treatment, and recruitment to clinical trials for miRNA-based drug therapy already underway. Electrochemical detection of biomarkers in urine has several significant advantages over circulating biomarker analysis including safety, cost, speed and ease of conversion to the point of care environment...
December 2017: Sensors and Actuators. B, Chemical
https://www.readbyqxmd.com/read/29199996/antisense-oligonucleotides-offer-hope-to-patients-with-charcot-marie-tooth-disease-type-1a
#14
Michael E Shy
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common heritable peripheral neuropathy and results from a duplication on chromosome 17 that results in an extra copy and increased dosage of peripheral myelin protein 22 (PMP22). Zhao et al., in this issue of the JCI, successfully utilized antisense oligonucleotides (ASOs) to reduce PMP22 and ameliorated neuropathy in both mouse and rat models of CMT1A. These data confirm that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A and lay the groundwork for clinical trials in humans afflicted with this chronic, debilitating neurodegenerative disease...
December 4, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29196820/functional-roles-of-agmatinase-during-the-peri-implantation-period-of-pregnancy-in-sheep
#15
Yasser Y Lenis, Mohammed A Elmetwally, Wanjin Tang, Carey Satterfield, Kathrin Dunlap, Guoyao Wu, Fuller W Bazer
This study investigated the effect of agmatine (Agm) in proliferation of ovine trophecdoderm cells (oTr1) as well as the importance of the arginine decarboxylase (ADC) and agmatinase (AGMAT) alternative pathway for synthesis of polyamines in ovine conceptuses during the peri-implantation period of pregnancy. Morpholino antisense oligonucleotides (MAOs) were used to inhibit translation of mRNAs for ODC1 alone, AGMAT alone, and their combination. Rambouillet ewes (N = 50) were assigned randomly to the following treatments on Day 8 of pregnancy: MAO control (n = 10); MAO-ODC1 (n = 8); MAO-ADC (n = 6); MAO-ODC1:MAO-ADC (n = 9); or MAO-ODC1:MAO-AGMAT (n = 9)...
December 2, 2017: Amino Acids
https://www.readbyqxmd.com/read/29192260/antisense-oligonucleotides-the-next-frontier-for-treatment-of-neurological-disorders
#16
REVIEW
Carlo Rinaldi, Matthew J A Wood
Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies...
December 1, 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29190672/first-in-human-phase-i-study-of-isth0036-an-antisense-oligonucleotide-selectively-targeting-transforming-growth-factor-beta-2-tgf-%C3%AE-2-in-subjects-with-open-angle-glaucoma-undergoing-glaucoma-filtration-surgery
#17
Norbert Pfeiffer, Bogomil Voykov, Giulia Renieri, Katharina Bell, Paul Richter, Melanie Weigel, Hagen Thieme, Barbara Wilhelm, Katrin Lorenz, Martin Feindor, Katja Wosikowski, Michel Janicot, Daniela Päckert, Regina Römmich, Carola Mala, Petra Fettes, Eugen Leo
PURPOSE: To evaluate the safety and tolerability of intravitreal ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in patients with primary open angle glaucoma (POAG) undergoing trabeculectomy (TE; glaucoma filtration surgery). METHODS: In this prospective phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC) received a single intravitreal injection of ISTH0036 at the end of surgery in escalating total doses of 6...
2017: PloS One
https://www.readbyqxmd.com/read/29188506/design-and-in-vitro-use-of-antisense-oligonucleotides-to-correct-pre-mrna-splicing-defects-in-inherited-retinal-dystrophies
#18
Alejandro Garanto, Rob W J Collin
Antisense oligonucleotides (AONs) are small molecules able to bind to the pre-mRNA and modulate splicing. The increasing amount of intronic mutations leading to pseudoexon insertion in genes underlying inherited retinal dystrophies (IRDs) has highlighted the potential of AONs as a therapeutic tool for these disorders. Here we describe how to design and test AON molecules in vitro in order to correct pre-mRNA splicing defects involved in IRDs.
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29185862/the-effects-of-2-o-methoxyethyl-oligonucleotides-on-renal-function-in-humans
#19
Stanley T Crooke, Brenda F Baker, Nguyen C Pham, Steven G Hughes, T Jesse Kwoh, Danlin Cai, Sotirios Tsimikas, Richard S Geary, Sanjay Bhanot
Systemically administered 2'-O-methoxyethyl (2'MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2'MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2'MOE ASO-treated patients at doses >175 mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate...
November 29, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29180822/damage-induced-lncrnas-control-the-dna-damage-response-through-interaction-with-ddrnas-at-individual-double-strand-breaks
#20
Flavia Michelini, Sethuramasundaram Pitchiaya, Valerio Vitelli, Sheetal Sharma, Ubaldo Gioia, Fabio Pessina, Matteo Cabrini, Yejun Wang, Ilaria Capozzo, Fabio Iannelli, Valentina Matti, Sofia Francia, G V Shivashankar, Nils G Walter, Fabrizio d'Adda di Fagagna
The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends...
November 27, 2017: Nature Cell Biology
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