It is crucial that the ASOs do not bind, even partially, to a nontarget mRNA. Front. (1997). We can illustrate this point by turning our attention to two specific examples: alternative splicing and non-coding RNAs. An example is the addition of N-acetylgalactosamine (GalNAc) to the RNA, thus enhancing asialoglycoprotein receptor (ASGR)-mediated uptake into liver hepatocytes (Nair etal., 2014). Transforming growth factor-beta in T-cell biology. as macromolecular drugs). Song S., Wang L., Li J., Fan C., Zhao J. Aptamer-based biosensors.
8600 Rockville Pike (A) Chemical model of a PNA molecule (sequence N-GTA-C) hybridized in antiparallel orientation with its complementary DNA (sequence 5-TAC-3). Rev. Such oligonucleotides are commonly synthesized using solid-phase chemistry. All Rights Reserved, Photosynthesis Photolysis and Carbon Fixation. Giovannelli I., Martelli F., Repice A., Massacesi L., Azzi A., Giannecchini S. Detection of JCPyV microRNA in blood and urine samples of multiple sclerosis patients under natalizumab therapy. GM designed and drafted the paper. (2005). Therefore, the therapeutic development of alicaforsen in CD was discontinued. 20, 295304. They work by binding to target mRNAs, generally (but not exclusively) to 3UTRs (the untranslated sequence that follows the stop codon in mRNAs). Wahlestedt, C., Salmi, P., Good, L., Kela, J., Johnsson, T., Hokfelt, T., et al. Novel convenient syntheses of LNA [2.2.1]bicyclo nucleosides. systematic evolution of ligands by exponential enrichment, signal transducer and activator of transcription 3. Analysis of 13 cell typesreveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. about navigating our updated article layout. It will also highlight how the invention of synthetic oligonucleotides such as peptide nucleic acid (PNA) or locked nucleic acid (LNA) has pushed the limits of molecular biology and biosensor development to new perspectives. Each monomeric unit component is comprised of a nucleobase, a pentose moiety, and phosphate group. In molecular genetics, they refer to a short sequence synthesised to match a regionwhere a mutation is known to occur, and then used as a probe (oligonucleotide probes). Immunol. While both purines and pyrimidines are heterocyclic aromatic compounds, they can be differed from each other based on the chemical structure. doi: 10.1111/apt.12051, Zuker, M. (2003). From DNA biosensors to gene chips. Briones C., Moreno M. Applications of peptide nucleic acids (PNAs) and locked nucleic acids (LNAs) in biosensor development.
doi: 10.1111/j.1365-2036.2006.02837.x, Monteleone, G., Fantini, M. C., Onali, S., Zorzi, F., Sancesario, G., Bernardini, S., et al. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: a case series.
Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic non-coding RNAs. Alternative splicing: global insights. Ther. Kohlmaier A., Savarese F., Lachner M., Martens J., Jenuwin T., Wutz A. Novel target site for antisense design. The duplex is then complexed by Argonaute and other proteins forming mature microribonucleoprotein (miRNP) complexes (also referred to as miRNA-induced silencing complex (miRISC)) in which only the guide strand of the miRNA is retained. Jangi M., Sharp P.A. doi: 10.1093/ibd/izy062, Jabs, D. A., and Griffiths, P. D. (2002). 28, 13401347. (2018). Inflammatory bowel disease. GM has filed a patent related to the treatment of IBD with Smad7 antisense oligonucleotides.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The content on this website is for information only. 23, 14031413. Further complexity arises from the presence of occasional alternative translation start codons. Knockdown of Smad7 with a specific antisense oligonucleotide attenuates colitis and colitis-driven colonic fibrosis in mice. HER216 forms a constitutively active dimer that is implicated in Herceptin resistance [6]. Mitra D., Brumlik M.J., Okamgba S.U., Zhu Y., Duplessis T.T., Parvani J.G., et al. Mapping of RNA accessible sites for antisense experiments with oligonucleotide libraries. This review will shed light on various typesof nucleic acids such as DNA and RNA (particularly microRNAs), their role and their application in biosensing. The fundamental nucleotides are divided into purines and pyrimidines. Thus, they are used basically in forensics, genetic testing, and research. Genes can even produce thousands of transcripts; a famous example is the fruitfly Dscam gene [5]. Aliment. The drug, named mongersen (previously called GED-0301), (Monteleone etal., 2012; Laudisi etal., 2016), was formulated in order to maximize the active compound release into the lumen of the terminal ileum and right colon, the intestinal regions mainly involved in CD. Invest. Biotechnol. Similar negative results were also obtained in two subsequent placebo-controlled phase III trials, in which alicaforsen was given to moderate-to-severe active CD patients (Yacyshyn etal., 2007). DNA-based biosensors can be used for a wide range of applications, from genetic identification to pathogen detection and disease diagnosis in biomedical, environmental and forensic applications. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. microRNAs (miRNAs)). will also be available for a limited time. The process, called alternative splicing, in which exons are joined together in different ways, results in several transcripts with potentially different coding potential. An overview of sugar-modified oligonucleotides for antisense therapeutics. Inflamm. The late stage of inflammation in IBD is characterized by the fibrotic process, which derives from an altered balance between matrix deposition and degradation (Rieder etal., 2017). Interestingly, LNA nucleotides can be easily mixed with DNA or RNA molecules in the oligonucleotide sequence, which greatly improves the thermal stability of LNADNA or LNAmiRNA duplexes. Degradation of mRNA is also highly regulated in response to developmental and physiological cues. Building robust transcriptomes with master splicing factors. The use of natural and synthetic nucleotides is still developing and paves the way towards advanced biosensor development. A., Gunawan, M. I., Hewlett, B., Bercik, P., Van Kampen, C., Galeazzi, F., et al. What follows is a brief overview of the complexities of gene expression. This has led to a range of bioassay methods that rely on aptamers as bioreceptors. LNA was first synthesized by both Obika et al. Gastroenterology 152, 340350.e346. Sharma, V. K., and Watts, J. K. (2015). It is, however, noteworthy that nanoparticles can increase the toxicity of the compound or alter pharmacokinetics and biodistribution of the silencing RNAs. Antisense oligonucleotides are DNA or RNA strands that are used in antisense therapy. Tanowitz, M., Hettrick, L., Revenko, A., Kinberger, G. A., Prakash, T. P., and Seth, P. P. (2017). Several hurdles need to be overcome including the problems associated with specificity and the need for efficient delivery to target tissues. Djebali S., Davis C.A., Merkel A., Dobin A., Lassmann T., Mortazavi A., et al. Oligonucleotide therapeutics: chemistry, delivery and clinical progress. In mild to moderate left-sided UC patients, alicaforsen enema had no significant effect on the course of the disease (Miner etal., 2006; Van Deventer etal., 2006). However, multiple HER2 splice isoforms have been reported.
Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohns disease. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts. 33, 533540. In the natural world, oligonucleotides exist mainly as small non-coding RNAs (e.g. They can be used in knocking down a gene function.
Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. 10:305. doi: 10.3389/fphar.2019.00305. Peptide nucleic acids and locked nucleic acids are examples of novel synthetic DNA/RNA analogues that can provide higher sensitivity and selectivity in biosensors. They are considered as alternatives to antibodies, where they can bind to their targets by undergoing conformational changes [15]. Phosphorothioates, essential components of therapeutic oligonucleotides. miRNAs are involved in plant and animal physiology and development. Exp. Dev.
Today 23, 101114. STNM01, a synthetic, double-stranded RNA oligonucleotide directed against CHST15, ameliorated acute and chronic DSS induced-colitis and reduced colonic deposition of collagen in mice (Suzuki etal., 2016). Nat. Invest. (2003). Activation of nuclear factor kappa B inflammatory bowel disease. In the early days of molecular biology, it was thought that transcriptional control was the main mechanism through which gene expression is controlled. In pre-mRNA splicing, sequences known as introns are precisely removed (spliced) and exons joined together to form the mature mRNA. Endoscopic improvement was observed in 37% of participants. Apart from the long chain of nucleic acids, nucleotides also occur in cyclic forms. In order to regulate target gene expression, these compounds have to reach disease-associated tissues and cross cell membranes. The increasing demand for enhanced efficiency and to overcome some of the drawbacks of using naturally occurring oligonucleotides has enabled biochemists to come up with synthetic analogues such as PNA and LNA, which have further increased the prospects of novel biosensing approaches. We here shortly review the basic concepts underlying the mechanism of action of the ASOs and summarize the available data for ASO-based therapy in IBD. The body is comprised of different elements with hydrogen, oxygen, carbon, and nitrogen as the major four. Wang J. DNA biosensors based on peptide nucleic acid (PNA) recognition layers. CHST15 is increased in the colon of active CD patients (Belmiro etal., 2005; Suzuki etal., 2016, 2017). [22] demonstrate how the neutral charge of PNA can be exploited with electrochemical impedance spectroscopy: whereas DNA probes on an electrode offer high resistance to negatively charged redox markers in solution [23], neutral PNA probes do not; upon binding with the complementary strand, a massive increase in resistance was observed because of the addition of negative charges and increased binding efficiency compared with DNADNA. doi: 10.1159/000484979, Hagedorn, P. H., Persson, R., Funder, E. D., Albaek, N., Diemer, S. L., Hansen, D. J., et al. Am. Moreover, it has also been demonstrated that the stability of a PNADNA duplex is essentially independent of the ionic strength of the buffer in which hybridization is performed [20]. J. Med. A., Witztum, J. L., Tsimikas, S., and Kastelein, J. J. P. (2016). FOIA This process is triggered mainly by chemoattractants produced within the inflamed tissue and favored by interaction between integrins expressed on leukocyte surface and proteins expressed on endothelial cells, such members of immunoglobulin superfamily [i.e. Nature 390, 465471.
Moreover, reductions in high-sensitivity C-reactive protein levels and fecal calprotectin were observed in patients with increased values at baseline (Feagan etal., 2018).
There are an increasing number of applications that have been developed for oligonucleotide-based biosensing systems in genetics and biomedicine.
Oligonucleotides are short DNA or RNA molecules. Developments in biochemistry and molecular biology have led to a deeper understanding of the role of oligonucleotides and showed that the functions they play are far greater than originally expected. Chem. The anti-inflammatory mechanism of TGF-1 relies mainly on the intracellular phosphorylation and subsequent activation of TGF-1 receptor-associated Smad2/3 proteins (Heldin etal., 1997; Shi and Massague, 2003). An alicaforsen-containing enema formulation was developed for patients with UC or patients with pouchitis, an inflammatory condition of the ileal pouch reservoir, which can develop in UC patients undergoing colectomy and ileal pouch-anal anastomosis. Castelnuovo M., Stutz F. Role of chromatin, environmental changes and single cell heterogeneity in non-coding transcription and gene regulation. doi: 10.1093/nar/28.6.1340. doi: 10.1053/gast.1996.v110.pm8613031, Belmiro, C. L. R., Souza, H. S. P., Elia, C. C. S., Castelo-Branco, M. T. L., Silva, F. R., Machado, R. L., et al. Future Med. They can be used to modify and monitor gene expression both in basic research and in gene therapy.
DNA that is packaged by proteins such as histones (or by protamines in sperm cells) is called chromatin. Making sense of antisense oligonucleotides: a narrative review. This has contributed in identifying novel druggable targets, thus offering interesting therapeutic perspectives for the treatment of these patients. 289, G116G128. 27, 7077. doi: 10.1093/nar/gkx960, Tatiparti, K., Sau, S., Kashaw, S. K., and Iyer, A. K. (2017). Signal transducer and activator of transcription 3 (STAT3) is involved in the activation of several oncogenic pathways. The site is secure. Because of its unique physico-chemical and biochemical properties, PNA as a bioreceptor opens up many applications (biological and diagnostic) which would not be achievable with naturally occurring oligonucleotides. Chemical modifications of the sugarphosphate backbone or the bases are often used to increase the stability and half-life of oligonucleotides. The Oligomers are also important for use in antisense therapy. Med. Such a modification changes the negative charges of the DNA sugarphosphate backbone to a neutral charge of the peptide-like backbone. The next section will give an overview on how synthetic oligonucleotides, such as PNA and LNA, can be transferred from in-solution application to on-surface biosensing applications. 1Department of Electronic and Electrical Engineering, University of Bath, Bath BA2 7AY, U.K. 2Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, U.K. Chem. Among these, antisense technology is a specific, rapid, and potentially high-throughput approach for inhibiting gene expression through recognition of cellular RNAs. Progress in antisense technology. Inflamm. This unique feature distinguishes them from other organisms Photosynthesis is the process that plants undertake to create organic materials from carbon dioxide and water, with the .. Before Oligonucleotide therapies for disorders of the nervous system. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Short non-coding RNAs include miRNAs are, when fully processed, quite small (21 nucleotides). An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Drug Metab. Mol. doi: 10.1172/JCI13885, Suzuki, K., Arumugam, S., Yokoyama, J., Kawauchi, Y., Honda, Y., Sato, H., et al. However, it is abundantly clear that epigenetics (including chemical modifications of DNA and of histones, affecting how DNA is packaged) and post-transcriptional control (pre-mRNA processing, mRNA localization, translation and stability) are equally important. GalNAc delivery is actually involved in several clinical and pre-clinical studies with exciting results (Tanowitz etal., 2017). J. Mol. Methylated DNA tends to be associated with genes that are less transcriptionally active. Other ASO-driven mechanisms include inhibition of 5 cap formation, alteration of splicing process (splice-switching), and steric hindrance of ribosomal activity (Chan etal., 2006; Bennett etal., 2017; Crooke, 2017). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Chem. mRNAs have a half-life; some are more stable than others and an mRNA's half-life has a bearing on how much protein is made. Antisense oligonucleotides: from design to therapeutic application. Another strategy to inhibit the expression of mRNA is represented by RNAi. In the last decades, the advent of new techniques of molecular and cellular biology has advanced our understanding of the factors/mechanisms that promote tissue damage in several chronic inflammatory diseases, including Crohns disease (CD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBDs) in humans (Neurath, 2017). Any information here should not be considered absolutely correct, complete, and up-to-date.
Z., Willis, J., West, G. A., Fiocchi, C., et al. This is because of the reduced electrostatic repulsion between PNA and DNA compared with DNA and DNA. [25] in 1997. The secondary and tertiary structure of the RNA must be taken into account to minimize the possibility that the selected sequence is inaccessible to binding (Ho etal., 1998; Vickers etal., 2000; Andronescu etal., 2005). Liver Physiol. J. Clin. Boirivant, M., Pallone, F., Di Giacinto, C., Fina, D., Monteleone, I., Marinaro, M., et al. 18, 816827. Celotto A.M., Graveley B.R. doi: 10.1053/j.gastro.2017.08.035, Gorelik, L., and Flavell, R. A. 31, 34063415.
microRNA). doi: 10.1053/j.gastro.2006.09.016, Burel, S. A., Hart, C. E., Cauntay, P., Hsiao, J., Machemer, T., Katz, M., et al. 45, 1238812400. (2017). The splice variant STAT3 arises from an alternative 3 splice site in exon 23; it encodes a truncated pro-apoptotic isoform (in contrast with the oncogenic STAT3 isoform). Gastrointest. This consists of a series of covalent modifications to the first base (the so-called trimethyl m7G cap). Rev. They work by repressing translation or even causing the targeted degradation of mRNAs (Figure 1). While STNM01 is the only siRNA currently tested in IBD, there is sufficient evidence to believe that RNAi technology can represent a new and valid approach to regulate the expression of disease-related genes. doi: 10.1016/j.jmb.2004.10.082, Babyatsky, M. W., Rossiter, G., and Podolsky, D. K. (1996). Regulation of homeostasis and inflammation in the intestine.
A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B. Gastroenterology 125, 17501761. Synthetic oligonucleotides or nucleic acid analogues are compounds which are structurally similar to naturally occurring RNA or DNA. doi: 10.1111/j.1749-6632.1998.tb11119.x, Neurath, M. F., Pettersson, S., Meyer Zum Buschenfelde, K. H., and Strober, W. (1996). Toxicol. doi: 10.1053/gast.2001.24015, Sedda, S., Marafini, I., Dinallo, V., Di Fusco, D., and Monteleone, G. (2015).
8600 Rockville Pike (A) Chemical model of a PNA molecule (sequence N-GTA-C) hybridized in antiparallel orientation with its complementary DNA (sequence 5-TAC-3). Rev. Such oligonucleotides are commonly synthesized using solid-phase chemistry. All Rights Reserved, Photosynthesis Photolysis and Carbon Fixation. Giovannelli I., Martelli F., Repice A., Massacesi L., Azzi A., Giannecchini S. Detection of JCPyV microRNA in blood and urine samples of multiple sclerosis patients under natalizumab therapy. GM designed and drafted the paper. (2005). Therefore, the therapeutic development of alicaforsen in CD was discontinued. 20, 295304. They work by binding to target mRNAs, generally (but not exclusively) to 3UTRs (the untranslated sequence that follows the stop codon in mRNAs). Wahlestedt, C., Salmi, P., Good, L., Kela, J., Johnsson, T., Hokfelt, T., et al. Novel convenient syntheses of LNA [2.2.1]bicyclo nucleosides. systematic evolution of ligands by exponential enrichment, signal transducer and activator of transcription 3. Analysis of 13 cell typesreveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. about navigating our updated article layout. It will also highlight how the invention of synthetic oligonucleotides such as peptide nucleic acid (PNA) or locked nucleic acid (LNA) has pushed the limits of molecular biology and biosensor development to new perspectives. Each monomeric unit component is comprised of a nucleobase, a pentose moiety, and phosphate group. In molecular genetics, they refer to a short sequence synthesised to match a regionwhere a mutation is known to occur, and then used as a probe (oligonucleotide probes). Immunol. While both purines and pyrimidines are heterocyclic aromatic compounds, they can be differed from each other based on the chemical structure. doi: 10.1111/apt.12051, Zuker, M. (2003). From DNA biosensors to gene chips. Briones C., Moreno M. Applications of peptide nucleic acids (PNAs) and locked nucleic acids (LNAs) in biosensor development.
doi: 10.1111/j.1365-2036.2006.02837.x, Monteleone, G., Fantini, M. C., Onali, S., Zorzi, F., Sancesario, G., Bernardini, S., et al. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: a case series.
Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic non-coding RNAs. Alternative splicing: global insights. Ther. Kohlmaier A., Savarese F., Lachner M., Martens J., Jenuwin T., Wutz A. Novel target site for antisense design. The duplex is then complexed by Argonaute and other proteins forming mature microribonucleoprotein (miRNP) complexes (also referred to as miRNA-induced silencing complex (miRISC)) in which only the guide strand of the miRNA is retained. Jangi M., Sharp P.A. doi: 10.1093/ibd/izy062, Jabs, D. A., and Griffiths, P. D. (2002). 28, 13401347. (2018). Inflammatory bowel disease. GM has filed a patent related to the treatment of IBD with Smad7 antisense oligonucleotides.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The content on this website is for information only. 23, 14031413. Further complexity arises from the presence of occasional alternative translation start codons. Knockdown of Smad7 with a specific antisense oligonucleotide attenuates colitis and colitis-driven colonic fibrosis in mice. HER216 forms a constitutively active dimer that is implicated in Herceptin resistance [6]. Mitra D., Brumlik M.J., Okamgba S.U., Zhu Y., Duplessis T.T., Parvani J.G., et al. Mapping of RNA accessible sites for antisense experiments with oligonucleotide libraries. This review will shed light on various typesof nucleic acids such as DNA and RNA (particularly microRNAs), their role and their application in biosensing. The fundamental nucleotides are divided into purines and pyrimidines. Thus, they are used basically in forensics, genetic testing, and research. Genes can even produce thousands of transcripts; a famous example is the fruitfly Dscam gene [5]. Aliment. The drug, named mongersen (previously called GED-0301), (Monteleone etal., 2012; Laudisi etal., 2016), was formulated in order to maximize the active compound release into the lumen of the terminal ileum and right colon, the intestinal regions mainly involved in CD. Invest. Biotechnol. Similar negative results were also obtained in two subsequent placebo-controlled phase III trials, in which alicaforsen was given to moderate-to-severe active CD patients (Yacyshyn etal., 2007). DNA-based biosensors can be used for a wide range of applications, from genetic identification to pathogen detection and disease diagnosis in biomedical, environmental and forensic applications. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. microRNAs (miRNAs)). will also be available for a limited time. The process, called alternative splicing, in which exons are joined together in different ways, results in several transcripts with potentially different coding potential. An overview of sugar-modified oligonucleotides for antisense therapeutics. Inflamm. The late stage of inflammation in IBD is characterized by the fibrotic process, which derives from an altered balance between matrix deposition and degradation (Rieder etal., 2017). Interestingly, LNA nucleotides can be easily mixed with DNA or RNA molecules in the oligonucleotide sequence, which greatly improves the thermal stability of LNADNA or LNAmiRNA duplexes. Degradation of mRNA is also highly regulated in response to developmental and physiological cues. Building robust transcriptomes with master splicing factors. The use of natural and synthetic nucleotides is still developing and paves the way towards advanced biosensor development. A., Gunawan, M. I., Hewlett, B., Bercik, P., Van Kampen, C., Galeazzi, F., et al. What follows is a brief overview of the complexities of gene expression. This has led to a range of bioassay methods that rely on aptamers as bioreceptors. LNA was first synthesized by both Obika et al. Gastroenterology 152, 340350.e346. Sharma, V. K., and Watts, J. K. (2015). It is, however, noteworthy that nanoparticles can increase the toxicity of the compound or alter pharmacokinetics and biodistribution of the silencing RNAs. Antisense oligonucleotides are DNA or RNA strands that are used in antisense therapy. Tanowitz, M., Hettrick, L., Revenko, A., Kinberger, G. A., Prakash, T. P., and Seth, P. P. (2017). Several hurdles need to be overcome including the problems associated with specificity and the need for efficient delivery to target tissues. Djebali S., Davis C.A., Merkel A., Dobin A., Lassmann T., Mortazavi A., et al. Oligonucleotide therapeutics: chemistry, delivery and clinical progress. In mild to moderate left-sided UC patients, alicaforsen enema had no significant effect on the course of the disease (Miner etal., 2006; Van Deventer etal., 2006). However, multiple HER2 splice isoforms have been reported. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohns disease. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts. 33, 533540. In the natural world, oligonucleotides exist mainly as small non-coding RNAs (e.g. They can be used in knocking down a gene function.
Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. 10:305. doi: 10.3389/fphar.2019.00305. Peptide nucleic acids and locked nucleic acids are examples of novel synthetic DNA/RNA analogues that can provide higher sensitivity and selectivity in biosensors. They are considered as alternatives to antibodies, where they can bind to their targets by undergoing conformational changes [15]. Phosphorothioates, essential components of therapeutic oligonucleotides. miRNAs are involved in plant and animal physiology and development. Exp. Dev.
Today 23, 101114. STNM01, a synthetic, double-stranded RNA oligonucleotide directed against CHST15, ameliorated acute and chronic DSS induced-colitis and reduced colonic deposition of collagen in mice (Suzuki etal., 2016). Nat. Invest. (2003). Activation of nuclear factor kappa B inflammatory bowel disease. In the early days of molecular biology, it was thought that transcriptional control was the main mechanism through which gene expression is controlled. In pre-mRNA splicing, sequences known as introns are precisely removed (spliced) and exons joined together to form the mature mRNA. Endoscopic improvement was observed in 37% of participants. Apart from the long chain of nucleic acids, nucleotides also occur in cyclic forms. In order to regulate target gene expression, these compounds have to reach disease-associated tissues and cross cell membranes. The increasing demand for enhanced efficiency and to overcome some of the drawbacks of using naturally occurring oligonucleotides has enabled biochemists to come up with synthetic analogues such as PNA and LNA, which have further increased the prospects of novel biosensing approaches. We here shortly review the basic concepts underlying the mechanism of action of the ASOs and summarize the available data for ASO-based therapy in IBD. The body is comprised of different elements with hydrogen, oxygen, carbon, and nitrogen as the major four. Wang J. DNA biosensors based on peptide nucleic acid (PNA) recognition layers. CHST15 is increased in the colon of active CD patients (Belmiro etal., 2005; Suzuki etal., 2016, 2017). [22] demonstrate how the neutral charge of PNA can be exploited with electrochemical impedance spectroscopy: whereas DNA probes on an electrode offer high resistance to negatively charged redox markers in solution [23], neutral PNA probes do not; upon binding with the complementary strand, a massive increase in resistance was observed because of the addition of negative charges and increased binding efficiency compared with DNADNA. doi: 10.1159/000484979, Hagedorn, P. H., Persson, R., Funder, E. D., Albaek, N., Diemer, S. L., Hansen, D. J., et al. Am. Moreover, it has also been demonstrated that the stability of a PNADNA duplex is essentially independent of the ionic strength of the buffer in which hybridization is performed [20]. J. Med. A., Witztum, J. L., Tsimikas, S., and Kastelein, J. J. P. (2016). FOIA This process is triggered mainly by chemoattractants produced within the inflamed tissue and favored by interaction between integrins expressed on leukocyte surface and proteins expressed on endothelial cells, such members of immunoglobulin superfamily [i.e. Nature 390, 465471.
Moreover, reductions in high-sensitivity C-reactive protein levels and fecal calprotectin were observed in patients with increased values at baseline (Feagan etal., 2018).
There are an increasing number of applications that have been developed for oligonucleotide-based biosensing systems in genetics and biomedicine.
Oligonucleotides are short DNA or RNA molecules. Developments in biochemistry and molecular biology have led to a deeper understanding of the role of oligonucleotides and showed that the functions they play are far greater than originally expected. Chem. The anti-inflammatory mechanism of TGF-1 relies mainly on the intracellular phosphorylation and subsequent activation of TGF-1 receptor-associated Smad2/3 proteins (Heldin etal., 1997; Shi and Massague, 2003). An alicaforsen-containing enema formulation was developed for patients with UC or patients with pouchitis, an inflammatory condition of the ileal pouch reservoir, which can develop in UC patients undergoing colectomy and ileal pouch-anal anastomosis. Castelnuovo M., Stutz F. Role of chromatin, environmental changes and single cell heterogeneity in non-coding transcription and gene regulation. doi: 10.1093/nar/28.6.1340. doi: 10.1053/gast.1996.v110.pm8613031, Belmiro, C. L. R., Souza, H. S. P., Elia, C. C. S., Castelo-Branco, M. T. L., Silva, F. R., Machado, R. L., et al. Future Med. They can be used to modify and monitor gene expression both in basic research and in gene therapy.
DNA that is packaged by proteins such as histones (or by protamines in sperm cells) is called chromatin. Making sense of antisense oligonucleotides: a narrative review. This has contributed in identifying novel druggable targets, thus offering interesting therapeutic perspectives for the treatment of these patients. 289, G116G128. 27, 7077. doi: 10.1093/nar/gkx960, Tatiparti, K., Sau, S., Kashaw, S. K., and Iyer, A. K. (2017). Signal transducer and activator of transcription 3 (STAT3) is involved in the activation of several oncogenic pathways. The site is secure. Because of its unique physico-chemical and biochemical properties, PNA as a bioreceptor opens up many applications (biological and diagnostic) which would not be achievable with naturally occurring oligonucleotides. Chemical modifications of the sugarphosphate backbone or the bases are often used to increase the stability and half-life of oligonucleotides. The Oligomers are also important for use in antisense therapy. Med. Such a modification changes the negative charges of the DNA sugarphosphate backbone to a neutral charge of the peptide-like backbone. The next section will give an overview on how synthetic oligonucleotides, such as PNA and LNA, can be transferred from in-solution application to on-surface biosensing applications. 1Department of Electronic and Electrical Engineering, University of Bath, Bath BA2 7AY, U.K. 2Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, U.K. Chem. Among these, antisense technology is a specific, rapid, and potentially high-throughput approach for inhibiting gene expression through recognition of cellular RNAs. Progress in antisense technology. Inflamm. This unique feature distinguishes them from other organisms Photosynthesis is the process that plants undertake to create organic materials from carbon dioxide and water, with the .. Before Oligonucleotide therapies for disorders of the nervous system. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Short non-coding RNAs include miRNAs are, when fully processed, quite small (21 nucleotides). An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Drug Metab. Mol. doi: 10.1172/JCI13885, Suzuki, K., Arumugam, S., Yokoyama, J., Kawauchi, Y., Honda, Y., Sato, H., et al. However, it is abundantly clear that epigenetics (including chemical modifications of DNA and of histones, affecting how DNA is packaged) and post-transcriptional control (pre-mRNA processing, mRNA localization, translation and stability) are equally important. GalNAc delivery is actually involved in several clinical and pre-clinical studies with exciting results (Tanowitz etal., 2017). J. Mol. Methylated DNA tends to be associated with genes that are less transcriptionally active. Other ASO-driven mechanisms include inhibition of 5 cap formation, alteration of splicing process (splice-switching), and steric hindrance of ribosomal activity (Chan etal., 2006; Bennett etal., 2017; Crooke, 2017). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Chem. mRNAs have a half-life; some are more stable than others and an mRNA's half-life has a bearing on how much protein is made. Antisense oligonucleotides: from design to therapeutic application. Another strategy to inhibit the expression of mRNA is represented by RNAi. In the last decades, the advent of new techniques of molecular and cellular biology has advanced our understanding of the factors/mechanisms that promote tissue damage in several chronic inflammatory diseases, including Crohns disease (CD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBDs) in humans (Neurath, 2017). Any information here should not be considered absolutely correct, complete, and up-to-date.
Z., Willis, J., West, G. A., Fiocchi, C., et al. This is because of the reduced electrostatic repulsion between PNA and DNA compared with DNA and DNA. [25] in 1997. The secondary and tertiary structure of the RNA must be taken into account to minimize the possibility that the selected sequence is inaccessible to binding (Ho etal., 1998; Vickers etal., 2000; Andronescu etal., 2005). Liver Physiol. J. Clin. Boirivant, M., Pallone, F., Di Giacinto, C., Fina, D., Monteleone, I., Marinaro, M., et al. 18, 816827. Celotto A.M., Graveley B.R. doi: 10.1053/j.gastro.2017.08.035, Gorelik, L., and Flavell, R. A. 31, 34063415.
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A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B. Gastroenterology 125, 17501761. Synthetic oligonucleotides or nucleic acid analogues are compounds which are structurally similar to naturally occurring RNA or DNA. doi: 10.1111/j.1749-6632.1998.tb11119.x, Neurath, M. F., Pettersson, S., Meyer Zum Buschenfelde, K. H., and Strober, W. (1996). Toxicol. doi: 10.1053/gast.2001.24015, Sedda, S., Marafini, I., Dinallo, V., Di Fusco, D., and Monteleone, G. (2015).