PURPOSE: To examine the signal transduction pathways involved in the activation of orbital fibroblast effector functions relevant to the pathogenesis of Graves ophthalmopathy (GO). To determine, using antisense technology, whether the c-myc protooncogene is involved in cell proliferation and glycosaminoglycan (GAG) synthesis in cultured orbital fibroblasts (OF). METHODS: The effects of a 16-mer c-myc antisense phosphorothioate oligodeoxynucleotide (S-ODN) on OF monolayers derived from orbital connective tissue of patients with severe GO (n = 6) and healthy individuals (n = 3) were investigated. Quiescent OF monolayers were treated with serum or cytokines and were exposed to increasing concentrations of a c-myc antisense S-ODN and several control S-ODN. Cell proliferation was quantitated by direct cell counting and by immunocytochemistry for the nuclear Ki-67 antigen. Glycosaminoglycan synthesis was examined by [3H] GAG analysis. The effects of the c-myc antisense S-ODN and control S-ODN on ...
Antisense oligonucleotide is a new approach to treat several neurodegenerative disorders to prevent disease onset or stop disease development.
The reduction in IGF-IR seemed to result in a reduction in vascular AT1R (but not AT2R) expression in these animals. 125I-Sar1-Ile8 angiotensin II binding in the presence of PD123319, but not losartan, was reduced in antisense-treated rats. Antisense oligonucleotides do have nonsequence-specific and off-target effects, and in the current study, AT1R levels were lower in mismatch-treated rats than untreated rats. Thus, there may have been some small degree of nonspecific effect of oligonucleotide treatment on AT1R levels in this study, which a greater sample size could have revealed as statistically significant. However, there was indeed a significant difference between AT1R levels in antisense-treated rats compared with both forms of control-untreated and mismatch-treated rats. We can therefore conclude that IGF-I receptor knockdown does reduce AT1 receptor levels compared with relevant controls.. We were unable to accurately determine whether there was a greater antisense-mediated reduction in ...
One major challenge to antisense technology (and RNAi) is the difficulty of getting it into the body. Delivery of the treatment to the brain, for use in diseases like HD, is especially challenging because it must cross the blood-brain barrier. Brain entry is very difficult and cannot be accomplished through a simple injection or pill that contains the antisense oligos. Isis Pharmaceuticals, the leading company in antisense technology, plans to solve this problem by inserting a pump into the chest that can carry the drug to the brain through a catheter, or tube. Another possible solution is to use an inactivated virus to "infect" cells with the drug.. The second major challenge to antisense technology is its inevitable toxic effects. Although antisense technology is engineered to be very specific, it can still cause unintended damage because it would regulate both the mutant and normal Huntington alleles. The challenge is to determine the right dosage and composition of an antisense molecule to ...
Zuschriften DOI: 10.1002/ange.201104514 Delivery Platforms Oligonucleotide Delivery by Cell-Penetrating "Striped" Nanoparticles** Christopher M. Jewell, Jin-Mi Jung, Prabhani U. Atukorale, Randy P. Carney, Francesco Stellacci,* and Darrell J. Irvine* Gold nanoparticles (AuNPs) hold great interest in drug delivery because these materials can be functionalized with a range of biological cargos, induce minimal toxicity, and can be efficiently cleared from the body.[1] For example, many studies have described conjugation of DNA or RNA to particle surfaces in well-defined configurations, and these materials have been applied in numerous biological and therapeutic settings.[1, 2] Devising new ways to mediate cell entry by AuNPs is a central area of interest. When mixed self-assembled monolayers of dislike molecules are used to coat AuNPs, nanoscale domains spontaneously form in the particles ligand shell. In particular, "stripe-like" domains form for ca. 1:1 binary mixed ligand compositions.[3] The ...
We have examined the antisense potency of the hybrid duplexes of fully-matched 3-, 5 and interior-chromophore tethered antisense oligos (AON) and three target RNAs (11mer and two 17mers) against RNase H, and found them to be better substrates compared t. ...
Dear Chen, There is probably no guarantee that a sequence will work. I had good experiences with full phosphorothioates (PTOs, nice if you have your own synthesizer, if not, have at least four or five phosphorothioates at the ends). PTOs are more stable than normal DNAs, commercial snthesis is expensive though, because the thioation step is time consuming. Another point of consideration might be that your target sequence is accessible for the oligo and for RNAse H. Look at secondary structure plots of the mRNA sequence and pick out regions that are in loops, not in stems. Binding to stems might enhance stability of mRNA by triplex formation. (These ideas are open for discussion!). Leave the trityl protecting group on the molecule, it will make it easier for the oligo to enter the cells. Intracellularily, it will be cleaved off. General considerations for PCR primers might be applicable to antisense oligos, too. Having (GCs) at the ends might stabilize complexes more than (ATs). Theres a good ...
Gymnosis combines specifically modified antisense oligos with a cells normal growth properties to achieve sequence-specific target knockdown without the need for transfection reagents or serum additives, according to its developers.
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the U.S. Improvements in therapy have increased the survival of patients with CRC from 10 months to two years, but for patients who stop responding to treatments, such as irinotecan, options for additional therapy are limited. Antisense oligonucleotides (ASOs) may offer advantages over traditional therapies if an appropriate target can be identified.
Antisense oligos containing phosphorothioate bonds can be used in medium containing serum. However, it is recommended that you inactivate the exonucleases in the serum to decrease the chances of degredation even when protecting modifications (such as phosphorothioate bonds) are present. Exonuclease inactivation can be accomplished by heat inactivatation at 65°C (instead of 56°C) for 30 minutes. The half life of such an antisense oligo will be dependent on the target transcript, the cell type, and the antisense construct, resulting in no set average for this number. There are reports of antisense oligos lasting 24 hours in vivo (mice ...
An improved delivery system for antisense oligonucleotides involves a liposomal composition, comprising a liposome which consists essentially of neutral phospholipids and an antisense oligonucleotide that is entrapped in the liposome and is selected from the group consisting of phosphodiester oligonucleotides, phosphorothioate oligonucleotides, and p-ethoxy oligonucleotides.
Compositions of antisense oligonucleotides conjugated to peptides of a plurality of N-methylpyrrolecarboxamides linked by peptide bonds is provided. The compositions form stable hybridization complexes with DNA and can be used for any purpose which involves hybridizing an oligonucleotide to a DNA molecule, such as in antisense procedures. A method for enhancing oligonucleotide binding to a target is also provided. The method involves the step of hybridizing the target DNA with an oligonucleotide-peptide composition.
Title: Modification of Alternative Splicing by Antisense Oligonucleotides as a Potential Chemotherapy for Cancer and Other Diseases. VOLUME: 1 ISSUE: 3. Author(s): D. R. Mercatante, P. Sazani and R. Kole. Affiliation:University of North Carolina, Lineberger Comprehensive Cancer Center, CB᱿, Chapel Hill.. Abstract: It has been estimated that greater than 35% of all human genes undergo alternative splicing. The process of alternative splicing is highly regulated and disruption of a splicing pattern can produce splice variants that have different functions. Certain splice variants that are associated with induction of cell death, regulation of cellular proliferation and differentiation, cell signaling, and angiogenesis are present in a variety of cancers. Several of these cancer-related alternatively spliced genes will be discussed in this review. In addition, alternative splicing is associated with several genetic disorders such as β-thalassemia, cystic fibrosis, and muscular dystrophy. Control ...
OBJECTIVE Reductions of Kinesin-1 by antisense oligonucleotides, or overexpression of dominant-negative performing kinesin large string, offers been reported to have an effect on the sustained stage of glucose-stimulated insulin release in -cells in vitro. structure, or -cell size. Nevertheless, likened with handles, pancreas of rodents displayed both decreased islet size and elevated amount islet, concomitant with an elevated insulin vesicle thickness in -cells. A conclusion In addition to getting important for preserving blood sugar homeostasis and controlling -cell function, Kif5c might end up being involved in -cell advancement by controlling -cell insulin and growth vesicle activity. Insulin is normally solely created and secreted from pancreatic -cells in two distinctive stages in response to raised bloodstream blood sugar amounts. The initial stage of insulin discharge is normally prompted by 1047645-82-8 a speedy boost of intracellular calcium supplement level leading to blend of ...
Efficient Nuclear Delivery of Antisense Oligonucleotides or siRNA In Vitro and In Vivo by Nano-Transforming Polymersomes - diagram, schematic, and image 02 ...
The Report Antisense Oligonucleotides Market: Global Industry Analysis 2013-2017 and Opportunity Assessment 2018-2028 provides information on pricing, market analysis, shares, forecast, and company profiles for key industry participants. - MarketResearchReports.biz
For knockdown, you can deliver antisense oligos into cells or use molecules that trigger the RNAi pathway such as siRNA or shRNA. The most specific approach is to deliver steric-blocking antisense oligos, which do not use enzymatic systems like argonaute or RNAse-H. Steric-blocking oligos have longer complementarity requirements for knockdowns. Steric-blocking oligos have modified backbones which do not trigger RNase-H activity. These oligos include 2-O-methyl RNA, locked nucleic acids (LNA), peptide nucleic acids (PNA) and Morpholino oligos. Different steric-blocking oligo types have different optimal delivery techniques, though any of them can be delivered into cell culture by electroporation. In-vivo delivery moieties have been developed to bring steric-blocking oligos into cells after systemic injection (e.g. i.v., i.p.) into adult animals ...
To characterize the role played by Na/Ca exchange in the pancreatic beta-cell, phosphorothioated antisense oligonucleotides (AS-oligos) were used to knock down the exchanger in rat pancreatic beta-cells. Na/Ca exchange activity was evaluated by measuring cytosolic free Ca2+ concentration ([Ca2+]i) in single cells using fura-2. Exposure of beta-cells to 500 nmol/l of the AS-oligos for 24 h inhibited Na/Ca exchange activity by approximately 77%. In contrast, control oligonucleotides (scrambled and mismatched) did not affect Na/Ca exchange activity. In AS-oligo-treated cells, the increase in [Ca2+]i induced by membrane depolarization (K+ or the hypoglycemic sulfonylurea, tolbutamide) was reduced by 28 or 40%, respectively. Likewise, the rate of [Ca2+]i decrease after K+ or tolbutamide removal was reduced by 72 or 40%, respectively. AS-oligos treatment also abolished the nifedipine-resistant increase in [Ca2+]i induced by K+ and profoundly altered the oscillatory or sustained increases in [Ca2+]i ...
Ionis Pharmaceuticals (formerly Isis Pharmaceuticals), in collaboration with AstraZeneca, is developing novel generation antisense therapeutics for the
The research report is a valuable tool for comprehending the progression of the global gene therapy and antisense drugs market between 2017 and 2025.
The research report is a valuable tool for comprehending the progression of the global gene therapy and antisense drugs market between 2017 and 2025.
Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker ...
Isis Pharmaceuticals has announced positive Phase II results in patients with Type 2 diabetes treated with ISIS 113715 as a single-agent. An intent-to-treat analysis of all patients enrolled in the trial treated with 200 mg/wk for three months showed statistically significant improvement in multiple measures of glucose control. ISIS 113715 did not cause hypoglycemia (low blood sugar), did not cause weight gain and was well tolerated. ISIS 113715, a second-generation antisense drug, is a novel insulin sensitizer that reduces the expression of protein tyrosine phosphatase-1B (PTP-1B). PTP-1B is a mediator of insulin resistance, one of two main defects in patients with Type 2 diabetes. ...
We have proposed previously that the RIα regulatory subunit of PKA-I is an ontogenic growth-inducing protein and that its constitutive expression disrupts normal ontogenic processes, resulting in a pathogenic outgrowth such as cancer (2) . The results presented here confirm this view and suggest that the RIα antisense, which works through the Watson-Crick base pairing mechanism of action, can serve as a single gene-based therapeutic agent for cancer. The sequence-specific mechanism of action of RIα antisense is strongly supported by the experimental data that MBO antisense, having an increased hybridizing capacity and nuclease resistance, increased the antisense effect of growth inhibition, whereas the mismatched MBO control oligos could not mimic the antisense effects.. In this study, minimization of the polyanionic nature of the PS-oligo and modifications of the immunostimulatory CpG motif were two important goals for us to demonstrate the sequence-specific antisense effects in the absence ...
One difference between metabolism in cancer and normal cells is the switch in cancer to the production of a different version, or isoform, of a protein produced from the pyruvate kinase-M (PK-M) gene. The protein version produced in normal cells is known as PK-M1, while the one produced by cancer cells is known as PK-M2.. PK-M2 is highly expressed in a broad range of cancer cells. It enables the cancer cell to consume far more glucose than normal, while using little of it for energy. Instead, the rest is used to make more material with which to build more cancer cells.. PK-M1 and PK-M2 are produced in a mutually exclusive manner - one-at-a-time, from the same gene, by a mechanism known as alternative splicing. When a genes DNA is being copied into the messenger molecule known as mRNA, the intermediate template for making proteins, a cellular machine called the spliceosome cuts and pastes different pieces out of and into that mRNA molecule.. The non-essential parts that are edited out are known ...
Today, Insights is synonymous with UPSC civil services exam preparation. Insights has redefined the way preparation is done in UPSC civil service exam. ...
The availability of the human genome sequence has revolutionized the strategy of employing nucleic acids with sequences complementary to specific target genes to improve drug discovery and target validation. Development of sequence-specific DNA or RNA analogs that can block the activity of selected single-stranded genetic sequences offers the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer, at relatively inexpensive costs. Antisense technology is one such example that has shown promising results and boasts of yielding the only approved drug to date in the genomics field. However, in vivo delivery issues have yet to be completely overcome for widespread clinical applications. In contrast to antisense oligonucleotides, the mechanism of silencing an endogenous gene by the introduction of a homologous double-stranded RNA (dsRNA), transgene or virus is called post-transcriptional gene silencing (PTGS) or RNA ...
An estimated 60% of all human genes undergo alternative splicing, a highly regulated process that produces splice variants with different functions. Such variants have been linked to a variety of cancers, and genetic diseases such as thalassemia and cystic fibrosis. This Perspective describes a promising approach to RNA repair based on the use of antisense oligonucleotides to modulate alternative splicing and engender the production of therapeutic gene products.. ...
Sequence specific interactions between nucleic acids, through Watson-Crick base pairing, or between nucleic acids and proteins, through well defined recognition rules, govern all steps of gene...
Molecular Cloning, also known as Maniatis, has served as the foundation of technical expertise in labs worldwide for 30 years. No other manual has been so popular, or so influential.
As in any clinical trial, this study included a number of endpoints. Endpoints are just the target, or goal, that you want your study to accomplish. In future HD trials, this might include things like improved movement or thinking. But for a new drug that has never been tested in people, the endpoint is always safety, safety, safety.. Formally, researchers say that safety is the primary endpoint of the study. This just means its the sole criteria well use to judge whether the trial is a success or failure. If the drug turns out to be unsafe, the trial fails. If there are no safety concerns, the study is a success.. While wed obviously like be able to tell whether a drug is safe and whether it helps HD symptoms at the same time, we cant achieve both goals in the course of a single study. This is because it takes large numbers of participants - many hundreds - to tell whether a drug is influencing HD symptoms. But for a safety study, we want to treat the smallest reasonable number of people to ...
Molecular Cloning, also known as Maniatis, has served as the foundation of technical expertise in labs worldwide for 30 years. No other manual has been so popular, or so influential.
Radiolabeling is an essential part of drug development. Using a radiolabeled compound, the ADME can be quantitatively determined. Most often...
Efficiently deliver an siRNA express... Modified CMV promoter efficiently expresses hairpin siRNAs ... Positive Control Oligonucleotide Insert and Negative Control Shutt... Efficient delivery of siRNA or an siRNA expre...Adenoviruses are popular gene delivery vehicles b...,Delivering,siRNA,Using,Adenoviral,Vectors,biological,advanced biology technology,biology laboratory technology,biology device technology,latest biology technology
Inhibition of translation initiation by antisense oligonucleotides via an RNase-H independent mechanism.: We have used alpha-oligomers as antisense oligonucleot
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
C. M. Jewell, Jung, J. - M., Atukorale, P. U., Carney, R. P., Stellacci, F., and Irvine, D. J., "Oligonucleotide Delivery by Cell-Penetrating "Striped" Nanoparticles", Angewandte Chemie-International Edition, vol. 50, no. 51, pp. 12312 - 12315, 2011. ...
C. M. Jewell, Jung, J. - M., Atukorale, P. U., Carney, R. P., Stellacci, F., and Irvine, D. J., "Oligonucleotide Delivery by Cell-Penetrating "Striped" Nanoparticles", Angewandte Chemie-International Edition, vol. 50, no. 51, pp. 12312 - 12315, 2011. ...
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For over 10 years now TriLink has offered cutting edge services to researchers in the fields of gene therapy, nucleoside chemotherapy, oligonucleotide therapy and diagnostics. TriLink specializes in the modification of oligonucleotides and nucleoside triphosphates. We provide a wide range of services from radioactive labeling to conjugation to custom research. With a proven track record of manufacturing challenging novel oligonucleotides and nucleotides, high-purity compounds and excellent technical support are the hallmarks of TriLink ...
The primary purpose of this study is to identify a dose of Liposome Entrapped c-raf Antisense Oligonucleotide Easy-to-Use (LErafAON-ETU) which maximizes potential benefits of the compound to patients with advanced cancer, without compromising their safety. This study will also assess the processing of LErafAON-ETU by the body over time. Patients will receive an intravenous infusion of LErafAON-ETU each week. Multiple blood samples will be taken for pharmacokinetic analysis during the first treatment; two samples will be taken during both the second and third treatments. Patients will be eligible to continue treatment until the occurrence of unacceptable toxicity or disease progression.. In LErafAON-ETU, antisense oligonucleotides specific to c-raf, are associated with liposomes, which are microscopic membrane-like structures created from lipids (fats). Raf-1 is a protein which plays a critical role in many aspects of cellular activation and growth. Therefore, it is thought to be an important ...
A targeted approach to treating toxoplasmosis, a parasitic disease, shows early promise in test-tube and animal studies, where it prevented the parasites from making selected proteins. When tested in newly infected mice, ...
... , McGonnell, I., Makarenkova, H. P., Patel, K., Tickle, C., Lorimer, J., Green, C. R. Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach Developmental Genetics 1999 24:33-42 DOI:10.1002/(sici)1520-6408(1999)24:1/ ...
ASO A DNA sequence, typically 15 to 25 nucleotides in length, designed to bind to a complementary sequence on a target RNA molecule. As a result, the protein product coded by that particular RNA is...
Basic Research: Scientists from every sector of research (government, academia, non-profit and industry) contribute to understanding the disease process, leading researchers to identify potential disease pathways as drug targets. This step is completed using a variety of experimental tools including biochemical analysis of proteins involved in the disease and model development using cell and animal models in the laboratory.. Drug Discovery: A variety of treatment approaches are in development for ALS including small molecule approaches, gene therapy approaches and antisense technologies. Researchers in industry and academia identify appropriate chemical entities based on pathways believed to be relevant to the disease. These chemical entities are selected from large screens of thousands of molecules. Those that appear to interact with the target of interest and can be identified by an appropriate read out are selected and further optimized. There are a variety of chemical properties that are ...
Preparations for transferring efficiently oligonucleotides necessary in antisense therapy or the like into animal cells so as to be useful in treatment for various diseases, which comprises a collagen as an essential component are provided.
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TY - JOUR. T1 - Efficient delivery of an antisense oligodeoxyribonucleotide formulated in folate receptor-targeted liposomes. AU - Chiu, Shih Jiuan. AU - Marcucci, Guido. AU - Lee, Robert J.. PY - 2006/3. Y1 - 2006/3. N2 - Background: Folate receptors (FRs) are cellular surface markers for numerous solid tumors and myeloid leukemias. The aim of this study was to develop an antisense oligodeoxyribonucleotide (ODN) carrier targeting FR-overexpressing cancer cells using folate (FA) as the targeting moiety. G3139, a phosphorothioate antisense ODN against human bcl2 mRNA, was evaluated in this study. Materials and Methods: G3139-containing liposomes were prepared using an ethanol dilution method. For the targeted formulation, 0.5 mol% of folate-PEG-DSPE was incorporated as a targeting ligand into cationic liposomes composed of DC-Chol/egg PC/PEG-DSPE at 25:65:10 mol/mol. Particle size and surface charge were measured and cellular uptake was assessed by fluorescence microscopy and flow cytometry. The ...