FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W961949223> ?p ?o ?g. }

• W961949223 endingPage "1818" @default.
• W961949223 startingPage "1810" @default.
• W961949223 abstract "Heart failure (HF) is the end result of a diverse set of causes such as genetic cardiomyopathies, coronary artery disease, and hypertension and represents the primary cause of hospitalization in Europe. This serious clinical disorder is mostly associated with pathological remodeling of the myocardium, pump failure, and sudden death. While the survival of HF patients can be prolonged with conventional pharmacological therapies, the prognosis remains poor. New therapeutic modalities are thus needed that will target the underlying causes and not only the symptoms of the disease. Under chronic cardiac stress, small noncoding RNAs, in particular microRNAs, act as critical regulators of cardiac tissue remodeling and represent a new class of therapeutic targets in patients suffering from HF. Here, we focus on the potential use of microRNA inhibitors as a new treatment paradigm for HF. Heart failure (HF) is the end result of a diverse set of causes such as genetic cardiomyopathies, coronary artery disease, and hypertension and represents the primary cause of hospitalization in Europe. This serious clinical disorder is mostly associated with pathological remodeling of the myocardium, pump failure, and sudden death. While the survival of HF patients can be prolonged with conventional pharmacological therapies, the prognosis remains poor. New therapeutic modalities are thus needed that will target the underlying causes and not only the symptoms of the disease. Under chronic cardiac stress, small noncoding RNAs, in particular microRNAs, act as critical regulators of cardiac tissue remodeling and represent a new class of therapeutic targets in patients suffering from HF. Here, we focus on the potential use of microRNA inhibitors as a new treatment paradigm for HF. MicroRNAs (miRs) are a family of small (19–25 nucleotide) single-stranded noncoding RNA molecules that regulate gene expression at the post-transcriptional level. Inhibition of gene expression occurs through complementary base pairing with sequences mainly located in the 3′ untranslated region (3′ UTR) of the target mRNA,1Ambros V The functions of animal microRNAs.Nature. 2004; 431: 350-355Crossref PubMed Scopus (9070) Google Scholar leading to translational repression or mRNA degradation (Figure 1). Key recognition elements comprise nucleotides 2–8 at the 5′ end of the microRNA and are known as seed sequences.2Kim VN MicroRNA biogenesis: coordinated cropping and dicing.Nat Rev Mol Cell Biol. 2005; 6: 376-385Crossref PubMed Scopus (1993) Google Scholar MicroRNAs can be represented as families, defined by conservation of their seed region, with conservation of sequences from nematodes through to humans, implying importance of function during evolution. Between 10–40% of human mRNAs are regulated by microRNAs whereby single microRNA species can regulate multiple mRNA targets and single microRNAs may contain several microRNA recognition sites in their 3′UTR.3Bartel DP MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (15899) Google Scholar Such complex regulatory networks can control key biological functions and alterations in microRNA expression are associated with numerous human pathologies such as cancer,4Ventura A Jacks T MicroRNAs and cancer: short RNAs go a long way.Cell. 2009; 136: 586-591Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar,5Nana-Sinkam SP Croce CM Clinical applications for microRNAs in cancer.Clin Pharmacol Ther. 2013; 93: 98-104Crossref PubMed Scopus (303) Google Scholar neurodegenerative,6Salta E De Strooper B Non-coding RNAs with essential roles in neurodegenerative disorders.Lancet Neurol. 2012; 11: 189-200Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar,7Pogue AI Hill JM Lukiw WJ MicroRNA (miRNA): sequence and stability, viroid-like properties, and disease association in the CNS.Brain Res. 2014; 1584: 73-79Crossref PubMed Scopus (30) Google Scholar metabolic,8Rottiers V Näär AM MicroRNAs in metabolism and metabolic disorders.Nat Rev Mol Cell Biol. 2012; 13: 239-250Crossref PubMed Scopus (880) Google Scholar,9Latreille M Hausser J Stützer I Zhang Q Hastoy B Gargani S et al.MicroRNA-7a regulates pancreatic β cell function.J Clin Invest. 2014; 124: 2722-2735Crossref PubMed Scopus (208) Google Scholar and cardiovascular diseases.10Olson EN MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease.Sci Transl Med. 2014; 6: 239ps3Crossref PubMed Scopus (192) Google Scholar,11Da Costa Martins PA De Windt LJ MicroRNAs in control of cardiac hypertrophy.Cardiovasc Res. 2012; 93: 563-572Crossref PubMed Scopus (120) Google Scholar In recent years, research has been aimed at targeting dysregulated microRNA expression as a novel way to modulate biological processes for benefit. Such modulation of microRNAs has proven successful in vivo through the use of antisense oligonucleotides (ASOs) or modified microRNA mimics such as plasmid or lentiviral vectors that carry microRNA sequences designed to deliver microRNAs to cells and tissues (Figure 1). Since available heart failure (HF) pharmacotherapy has only a marginal impact on long-term prognosis of the disease, there is both room and a need for the development of innovative bio-therapeutics. This review focuses on the current status of microRNA-based therapies in HF and highlights the potential use of ASOs as microRNA inhibitors for the treatment of cardiovascular diseases. A distinct set of differentially expressed microRNAs exists in the failing as compared to normal heart. miR-1, miR-25, miR-29, miR-30, miR-133, and miR-150 show downregulated expression, while miR-21, miR-23a, miR-125, miR-195, miR-199a/b, and miR-214 show increased expression in experimental and human HF. This altered expression pattern is associated with underlying mechanisms that lead to the disease state.12Ikeda S Kong SW Lu J Bisping E Zhang H Allen PD et al.Altered microRNA expression in human heart disease.Physiol Genomics. 2007; 31: 367-373Crossref PubMed Scopus (538) Google Scholar,13van Rooij E Marshall WS Olson EN Toward microRNA-based therapeutics for heart disease: the sense in antisense.Circ Res. 2008; 103: 919-928Crossref PubMed Scopus (347) Google Scholar,14Dirkx E Gladka MM Philippen LE Armand AS Kinet V Leptidis S et al.Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.Nat Cell Biol. 2013; 15: 1282-1293Crossref PubMed Scopus (110) Google Scholar A hallmark of HF development is pathological hypertrophy.15Levy D Garrison RJ Savage DD Kannel WB Castelli WP Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study.N Engl J Med. 1990; 322: 1561-1566Crossref PubMed Scopus (4852) Google Scholar,16Kannel WB Doyle JT McNamara PM Quickenton P Gordon T Precursors of sudden coronary death. Factors related to the incidence of sudden death.Circulation. 1975; 51: 606-613Crossref PubMed Scopus (392) Google Scholar Several microRNAs are reported to regulate prohypertrophic genes, including hypertrophy-associated calmodulin, NFAT, Mef2a, Gata4, and Hand2 and are thought to be key regulators in HF development.12Ikeda S Kong SW Lu J Bisping E Zhang H Allen PD et al.Altered microRNA expression in human heart disease.Physiol Genomics. 2007; 31: 367-373Crossref PubMed Scopus (538) Google Scholar,17Thum T Catalucci D Bauersachs J MicroRNAs: novel regulators in cardiac development and disease.Cardiovasc Res. 2008; 79: 562-570Crossref PubMed Scopus (299) Google Scholar,18Ikeda S He A Kong SW Lu J Bejar R Bodyak N et al.MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes.Mol Cell Biol. 2009; 29: 2193-2204Crossref PubMed Scopus (333) Google Scholar Therapeutic cardiac-targeted delivery of one such microRNA, miR-1, reversed pressure overload-induced cardiac hypertrophy and attenuated pathological remodeling.19Karakikes I Chaanine AH Kang S Mukete BN Jeong D Zhang S et al.Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.J Am Heart Assoc. 2013; 2: e000078Crossref Scopus (208) Google Scholar miR-133, clustered with miR-1, is also repressed during HF and its repression suffices to induce cardiac hypertrophy and increase expression of target mRNAs such as RhoA (GDP-GTP exchange protein regulating cardiac hypertrophy), Cdc42 (kinase implicated in hypertrophy), and Nelf-A/WHSC2 (nuclear factor involved in cardiogenesis).20Carè A Catalucci D Felicetti F Bonci D Addario A Gallo P et al.MicroRNA-133 controls cardiac hypertrophy.Nat Med. 2007; 13: 613-618Crossref PubMed Scopus (1505) Google Scholar In line, miR-133 overexpression inhibits experimentally induced hypertrophy. Likewise miR-199b, a direct target of the calcineurin/NFAT pathway, is increased in mouse and human HF, and in vivo inhibition of miR-199b with a specific antagomir reduced nuclear NFAT activity and caused marked inhibition of hypertrophy and fibrosis.21da Costa Martins PA Salic K Gladka MM Armand AS Leptidis S el Azzouzi H et al.MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling.Nat Cell Biol. 2010; 12: 1220-1227Crossref PubMed Scopus (276) Google Scholar An important feature in the process of myocardial infarction (MI) and subsequent systolic HF is myocardial fibrosis leading to abnormal mechanical stiffness and contractile dysfunction.22Berk BC Fujiwara K Lehoux S ECM remodeling in hypertensive heart disease.J Clin Invest. 2007; 117: 568-575Crossref PubMed Scopus (686) Google Scholar Members of the miR-29 family are implicated in this process as they show marked downregulation in the border zone surrounding the infarcted area.23van Rooij E Sutherland LB Thatcher JE DiMaio JM Naseem RH Marshall WS et al.Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.Proc Natl Acad Sci USA. 2008; 105: 13027-13032Crossref PubMed Scopus (1496) Google Scholar Downstream targets of miR-29 include proteins associated with the fibrotic response such as; extracellular matrix-related genes such as elastin (ELN), collagenase type 1 alpha 1–3 (COL1A1-3) and fibrillin 1 (FBN1). miR-21 is also related to a fibrogenic phenotype as it controls cardiac fibroblast proliferation by facilitating MAPK signaling through induction of Sprouty homolog 1 (SPRY1).24Thum T Gross C Fiedler J Fischer T Kissler S Bussen M et al.MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts.Nature. 2008; 456: 980-984Crossref PubMed Scopus (1933) Google Scholar MicroRNAs also regulate the repair response after MI, another key aspect of HF. This process prevents hypoxic damage through the induction of angiogenesis driven by the cytokines vascular endothelial growth factor and fibroblast growth factor.25Syed IS Sanborn TA Rosengart TK Therapeutic angiogenesis: a biologic bypass.Cardiology. 2004; 101: 131-143Crossref PubMed Scopus (62) Google Scholar The endothelial cell-specific miR-126 can regulate this response following MI by inhibition of negative regulators of the vascular endothelial growth factor pathway such as SPRED1 and PIK3R226Fish JE Santoro MM Morton SU Yu S Yeh RF Wythe JD et al.miR-126 regulates angiogenic signaling and vascular integrity.Dev Cell. 2008; 15: 272-284Abstract Full Text Full Text PDF PubMed Scopus (1339) Google Scholar and, therefore, positively impact neo-angiogenesis and counteract hypoxia. MicroRNAs also play a pathophysiological role during atherosclerotic plaque progression. In this context, downregulation of miR-24 induces plaque stability by promoting the invasion of macrophages with matrix metalloproteinase-14 proteolytic activity.27Di Gregoli K Jenkins N Salter R White S Newby AC Johnson JL MicroRNA-24 regulates macrophage behavior and retards atherosclerosis.Arterioscler Thromb Vasc Biol. 2014; 34: 1990-2000Crossref PubMed Scopus (90) Google Scholar In contrast, miR-126-null mice have reduced endothelial cell proliferation and exacerbated atherosclerosis and reconstitution of miR-126-5p was able to rescue endothelial cell proliferation and limit atherosclerosis.28Schober A Nazari-Jahantigh M Wei Y Bidzhekov K Gremse F Grommes J et al.MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1.Nat Med. 2014; 20: 368-376Crossref PubMed Scopus (472) Google Scholar Together, these studies establish microRNAs as key regulators of cardiovascular disease and identify them as potential therapeutic targets to treat human disease. To date, the regulatory role of specific microRNAs in cardiovascular disease has primarily been elucidated from loss- or gain-of-function studies in mouse models of disease.17Thum T Catalucci D Bauersachs J MicroRNAs: novel regulators in cardiac development and disease.Cardiovasc Res. 2008; 79: 562-570Crossref PubMed Scopus (299) Google Scholar ASOs have been the main pharmacological tools used to inhibit microRNA function in mouse disease models. Here, we speculate on the potential use of antimirs and their therapeutic potential for cardiovascular disease. ASOs were first discovered in 1987 and can be described as short, single-stranded chains of nucleotides that hybridize with complementary RNA sequences.29Lemaitre M Bayard B Lebleu B Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site.Proc Natl Acad Sci U S A. 1987; 84: 648-652Crossref PubMed Scopus (314) Google Scholar In the last 10 years, ASOs have also been used as tools to inhibit microRNA function (anti-microRNA oligonucleotides (AMOs)), based on Watson-Crick base pairing.30Boutla A Delidakis C Tabler M Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in Drosophila and the identification of putative target genes.Nucleic Acids Res. 2003; 31: 4973-4980Crossref PubMed Scopus (117) Google Scholar AMOs exert their activity through several mechanisms including RNase H-mediated RNA degradation where recognition of the RNA-AMO duplex by RNase H leads to cleavage of the RNA strand31Wu H Lima WF Zhang H Fan A Sun H Crooke ST Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs.J Biol Chem. 2004; 279: 17181-17189Crossref PubMed Scopus (237) Google Scholar or sterically blocking access to pre-mRNA and mRNA without degrading the RNA32Smith CC Aurelian L Reddy MP Miller PS Ts'o PO Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5.Proc Natl Acad Sci U S A. 1986; 83: 2787-2791Crossref PubMed Scopus (263) Google Scholar (Figure 1). Despite several publications analyzing decreased microRNA expression level as measure of effectiveness of AMO treatment, the question remains whether this is the most reliable evaluation method to determine efficacy of microRNA inhibition. For example, binding of an AMO to its target microRNA may interfere with its detection but, depending on the chemistry of the AMO used, be able to inhibit microRNA function without also inducing its degradation. An example of this is LNA and 2′-fluoro/2′-methoxyethyl modified AMOs, which can inhibit microRNA activity without decreasing mature microRNA expression levels.33Davis S Propp S Freier SM Jones LE Serra MJ Kinberger G et al.Potent inhibition of microRNA in vivo without degradation.Nucleic Acids Res. 2009; 37: 70-77Crossref PubMed Scopus (168) Google Scholar In such cases, evaluating microRNA target derepression as a secondary endpoint may also provide a valuable measure of AMO efficacy. Because AMOs must bind specific nucleotide sequences the rational design of high affinity antagonists is relatively straightforward. However, since several enzymes present in the organism rapidly recognize RNA-like structures, premature degradation of AMOs can limit their bioavailibility. In this context, chemical modifications of AMOs can be employed to alter their pharmacokinetic properties and enhance cellular uptake without loss of binding (Figure 2). Indeed, differently modified antisense microRNAs have been shown to directly inhibit microRNA function in vivo and the examples detailed herein clearly show the potential of antisense microRNAs to treat cardiovascular diseases. Theoretically, systemically delivered oligonucleotides are susceptible to enzymatic degradation by nucleases present in the bloodstream by the same mechanisms that regulate native RNA. Methylation of the hydroxyl group at the 2′ position of the ribose unit is a relatively simple and attractive approach to increase resistance to nuclease attack. The 2′-O-methyl (2′-OMe) AMOs have been increasingly used in the past decade and have proven in vivo efficacy. Besides enhanced resistance to nuclease attack, 2′-OMe ASOs show improved binding affinity to their corresponding microRNA sequence as compared to unmodified AMOs.28Schober A Nazari-Jahantigh M Wei Y Bidzhekov K Gremse F Grommes J et al.MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1.Nat Med. 2014; 20: 368-376Crossref PubMed Scopus (472) Google Scholar,33Davis S Propp S Freier SM Jones LE Serra MJ Kinberger G et al.Potent inhibition of microRNA in vivo without degradation.Nucleic Acids Res. 2009; 37: 70-77Crossref PubMed Scopus (168) Google Scholar,34Davis S Lollo B Freier S Esau C Improved targeting of miRNA with antisense oligonucleotides.Nucleic Acids Res. 2006; 34: 2294-2304Crossref PubMed Scopus (356) Google Scholar Let-7 was the first microRNA to be successfully silenced using this method in the nematode C. elegans.35Hutvágner G Simard MJ Mello CC Zamore PD Sequence-specific inhibition of small RNA function.PLoS Biol. 2004; 2: E98Crossref PubMed Scopus (568) Google Scholar To further enhance resistance to nuclease attack conferred by 2′-OMe modification, phosphorothioate moieties in the linking backbone have also been introduced. These sulphur analogues of phosphate can be incorporated near either the 5′ or 3′ and show, in combination with a 3′-cholesterol unit, enhanced AMO stability in cell cultures.36Wolfrum C Shi S Jayaprakash KN Jayaraman M Wang G Pandey RK et al.Mechanisms and optimization of in vivo delivery of lipophilic siRNAs.Nat Biotechnol. 2007; 25: 1149-1157Crossref PubMed Scopus (755) Google Scholar Krützfeldt et al.37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar explored the potential of 2′-OMe modification to modulate microRNA in vivo using regulation of miR-122, a microRNA involved in cholesterol synthesis in the liver, as a model system. Unmodified single-stranded AMO-122 had no effect on miR-122 expression levels, whereas unconjugated chemically altered RNA analogues, partially or fully modified with a phosphorothioate backbone and 2′-OMe modifications, had a partial effect.37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar Additional cholesterol-conjugation of the altered synthetic AMO (antagomir) was able to completely abolish endogenous miR-122 levels suggesting that the partial decrease in miR-122 expression by the unconjugated modified RNA analogues was due to microRNA-122-RNA duplex formation, whereas silencing miR-122 by the antagomir was the result of complete microRNA degradation.37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar High sequence specificity was demonstrated by introducing position specific mismatches. The use of fluorescently labeled antagomirs further showed that antagomir-microRNA interaction took place in the cytoplasmic compartment, upstream of the processing bodies (P-bodies),37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar sites that act as scaffolding centers for microRNA function. Administration of a miR-122-specific antagomir at a dose of 80 mg/kg for 3 consecutive days effectively reduced miR-122 expression levels in mice for a period of 23 days.37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar Moreover, antagomirs successfully abolished microRNA expression in a few cardiovascular studies (Figure 2). Antagomirs exhibit a broad biodistribution and can efficiently silence their target microRNAs in all tissues tested. Although they cannot cross the placental and blood–brain barriers, injection of antagomirs directly into the cortex efficiently reduced microRNA levels in the brain.37Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al.Silencing of microRNAs in vivo with ‘antagomirs’.Nature. 2005; 438: 685-689Crossref PubMed Scopus (3371) Google Scholar Another approach to increase the stability of AMOs is the combination of 2′-MOE (2′-O-methoxyethyl) with phosphorothioate modifications in the linking backbone. This method is similar to 2′-OMe modifications albeit using CH2CH2OCH3 protective groups rather than a simple CH3. The use of a library of 2′-MOE AMOs to investigate the biological importance of microRNAs identified several microRNAs involved in adipocyte differentiation. Effective silencing of miR-143, a microRNA that is upregulated in differentiating adipocytes,38Esau C Kang X Peralta E Hanson E Marcusson EG Ravichandran LV et al.MicroRNA-143 regulates adipocyte differentiation.J Biol Chem. 2004; 279: 52361-52365Crossref PubMed Scopus (869) Google Scholar reversed adipocyte differentiation in the liver. The same group also showed that silencing miR-122 in mice with a specific 2′-MOE RNA antagonist efficiently reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation and decreased hepatic fatty acid and cholesterol synthesis rates.39Esau C Davis S Murray SF Yu XX Pandey SK Pear M et al.miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.Cell Metab. 2006; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (1779) Google Scholar Interestingly, the results obtained by Esau et al.39Esau C Davis S Murray SF Yu XX Pandey SK Pear M et al.miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.Cell Metab. 2006; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (1779) Google Scholar suggest that each AMO may have different affinity for their corresponding microRNA, with some specific targets being maximally affected at very low doses and others being less responsive. Besides the 2′OMe and 2′MOE variations of RNA analogues, other RNA analogues containing substitutions at the same location within the ribose unit have been described. One such example is the 2′Fluoro modification, which has proven to be a potent inhibitor of both miR-122 and miR-21 in mice.33Davis S Propp S Freier SM Jones LE Serra MJ Kinberger G et al.Potent inhibition of microRNA in vivo without degradation.Nucleic Acids Res. 2009; 37: 70-77Crossref PubMed Scopus (168) Google Scholar,40Thum T Chau N Bhat B Gupta SK Linsley PS Bauersachs J et al.Comparison of different miR-21 inhibitor chemistries in a cardiac disease model.J Clin Invest. 2011; 121 (author reply 462): 461-462Crossref PubMed Scopus (92) Google Scholar However, ASOs containing 2′-fluoro modifications require further modification to make them resistant to nuclease attack by making single strand antagonists with a full phosphorothioate backbone or additional 2′ protective groups like 2′MOE.33Davis S Propp S Freier SM Jones LE Serra MJ Kinberger G et al.Potent inhibition of microRNA in vivo without degradation.Nucleic Acids Res. 2009; 37: 70-77Crossref PubMed Scopus (168) Google Scholar,34Davis S Lollo B Freier S Esau C Improved targeting of miRNA with antisense oligonucleotides.Nucleic Acids Res. 2006; 34: 2294-2304Crossref PubMed Scopus (356) Google Scholar,41Rayner KJ Esau CC Hussain FN McDaniel AL Marshall SM van Gils JM et al.Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.Nature. 2011; 478: 404-407Crossref PubMed Scopus (597) Google Scholar The pharmacokinetics of AMOs can also be modified by locked nucleic acid (LNA) modifications where the 2′-hydroxyl group is linked to the 4′ carbon atom of the sugar ring thereby forming a bicyclic sugar moiety. The linkage is preferably a methylene [CH2]n group bridging the 2′ oxygen atom with the 4′ carbon atom wherein n is 1 or 2. LNA-protected antisense RNAs exhibit extremely high thermal stability when hybridized with their corresponding RNA target molecules. In addition, LNA oligonucleotides display low toxicity at low doses, are highly soluble42Vester B Wengel J LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA.Biochemistry. 2004; 43: 13233-13241Crossref PubMed Scopus (574) Google Scholar and show excellent activity in targeting microRNAs. An LNA targeting miR-122 was the first of its kind to be validated in nonhuman primates causing a meaningful reduction in plasma cholesterol. Systemic delivery of an LNA in a physiological buffer resulted in a dose-dependent long-lasting and reversible decrease in total plasma cholesterol levels in African green monkeys, without any observed toxicities or histopathological changes.43Elmén J Lindow M Schütz S Lawrence M Petri A Obad S et al.LNA-mediated microRNA silencing in non-human primates.Nature. 2008; 452: 896-899Crossref PubMed Scopus (1417) Google Scholar Empirically, LNAs possess the thermodynamically strongest duplex formation with complementary target RNA of all the AMOs. As a result, biological activity is often obtained with very short (8–15 nt) LNA-protected RNA sequences. Another advantage of LNA-modified oligonucleotides is their high metabolic stability (partly explained by enhanced nuclease resistance), their small size, excellent mismatch discrimination, and lack of toxicity in nonhuman primates.43Elmén J Lindow M Schütz S Lawrence M Petri A Obad S et al.LNA-mediated microRNA silencing in non-human primates.Nature. 2008; 452: 896-899Crossref PubMed Scopus (1417) Google Scholar,44Weiler J Hunziker J Hall J Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?.Gene Ther. 2006; 13: 496-502Crossref PubMed Scopus (347) Google Scholar However, LNAs may also form tight double strand binding which can lead to off-target microRNA engagement with subsequent inhibition of nontargeted microRNAs or precursor microRNAs. Indeed, a large animal model study using an LNA against miR-92a also inhibited the very closely resembling miR-25,45Hinkel R Penzkofer D Zühlke S Fischer A Husada W Xu QF et al.Inhibition of microRNA-92a protects against ischemia/reperfusion injury in a large-animal model.Circulation. 2013; 128: 1066-1075Crossref PubMed Scopus (237) Google Scholar which has been shown to be associated with adverse effects in animal models of HF.14Dirkx E Gladka MM Philippen LE Armand AS Kinet V Leptidis S et al.Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.Nat Cell Biol. 2013; 15: 1282-1293Crossref PubMed Scopus (110) Google Scholar Direct hepatoxicity of LNA nucleotides has also been observed in vivo, where adverse effects have been related to the use of particular LNA-modified oligonucleotide sequences.46Swayze EE Siwkowski AM Wancewicz EV Migawa MT Wyrzykiewicz TK Hung G et al.Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.Nucleic Acids Res. 2007; 35: 687-700Crossref PubMed Scopus (305) Google Scholar Nevertheless, LNAs show promise as they are well tolerated in vivo and are currently being evaluated in human clinical trials. Recently, Lennox et al.47Lennox KA Owczarzy R Thomas DM Walder JA Behlke MA Improved Performance of Anti-miRNA Oligonucleotides Using a Novel Non-Nucleotide Modifier.Mol Ther Nucleic Acids. 2013; 2: e117Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar introduced a different approach to microRNA inhibition by using the non-nucleotide modifier ZEN (N,N-diethyl-4-((4-nitronaphthalen-1-yl)diazenyl) aniline unit) bound at various locations in the phosphate backbone of the RNA structure of oligonucleotide sequences. Using this ZEN modifier on both 5′and 3′terminal ends of 2′OMe modified AMOs resulted in full resistance against enzymatic degradation in serum and cell extracts and using miR-21 as an example demonstrated that ZEN modification was able to reduce AMOs to a length as short as 15-mers.47Lennox KA Owczarzy R Thomas DM Walder JA Behlke MA Improved Performance of Anti-miRNA Oligonucleotides Using a Novel Non-Nucleotide Modifier.Mol Ther Nucleic Acids. 2013; 2: e117Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar In vivo testing of ZEN-AMOs is currently in progress but preliminary data indicate no obvious toxicity after systemic administration in mice.47Lennox KA Owczarzy R Thomas DM Walder JA Behlke MA Improved Performance of Anti-miRNA Oligonucleotides Using a Novel Non-Nucleotide Modifier.Mol Ther Nucleic Acids. 2013; 2: e117Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar After successful subcutaneous delivery of RNAi therapeutics by conjugation to GalNAc (N-Acetylgalactosamine) sugar,48Akinc A Querbes W De S Qin J Frank-K" @default.
• W961949223 created "2016-06-24" @default.
• W961949223 creator A5032155254 @default.
• W961949223 creator A5037672131 @default.
• W961949223 creator A5051634757 @default.
• W961949223 creator A5072301907 @default.
• W961949223 creator A5083771722 @default.
• W961949223 creator A5086919788 @default.
• W961949223 date "2015-12-01" @default.
• W961949223 modified "2023-10-16" @default.
• W961949223 title "Antisense MicroRNA Therapeutics in Cardiovascular Disease: Quo Vadis?" @default.
• W961949223 cites W1939069213 @default.
• W961949223 cites W1963871104 @default.
• W961949223 cites W1964915623 @default.
• W961949223 cites W1968949098 @default.
• W961949223 cites W1972989638 @default.
• W961949223 cites W1974770318 @default.
• W961949223 cites W1976277922 @default.
• W961949223 cites W1978025728 @default.
• W961949223 cites W1986176461 @default.
• W961949223 cites W1987263725 @default.
• W961949223 cites W1989910375 @default.
• W961949223 cites W1994869675 @default.
• W961949223 cites W1999746960 @default.
• W961949223 cites W2008279667 @default.
• W961949223 cites W2010757394 @default.
• W961949223 cites W2014203167 @default.
• W961949223 cites W2014396492 @default.
• W961949223 cites W2014946489 @default.
• W961949223 cites W2019818589 @default.
• W961949223 cites W2022687771 @default.
• W961949223 cites W2027744584 @default.
• W961949223 cites W2033966391 @default.
• W961949223 cites W2047043150 @default.
• W961949223 cites W2048255670 @default.
• W961949223 cites W2051206320 @default.
• W961949223 cites W2052322311 @default.
• W961949223 cites W2060072724 @default.
• W961949223 cites W2060119915 @default.
• W961949223 cites W2062913557 @default.
• W961949223 cites W2070987614 @default.
• W961949223 cites W2072512782 @default.
• W961949223 cites W2073537048 @default.
• W961949223 cites W2073751243 @default.
• W961949223 cites W2079761894 @default.
• W961949223 cites W2080696342 @default.
• W961949223 cites W2080942582 @default.
• W961949223 cites W2083246499 @default.
• W961949223 cites W2086299962 @default.
• W961949223 cites W2086818182 @default.
• W961949223 cites W2088707712 @default.
• W961949223 cites W2090374150 @default.
• W961949223 cites W2101080348 @default.
• W961949223 cites W2103052577 @default.
• W961949223 cites W2104905829 @default.
• W961949223 cites W2107387191 @default.
• W961949223 cites W2110315980 @default.
• W961949223 cites W2111485250 @default.
• W961949223 cites W2113468928 @default.
• W961949223 cites W2113899452 @default.
• W961949223 cites W2114687536 @default.
• W961949223 cites W2116424844 @default.
• W961949223 cites W2117224856 @default.
• W961949223 cites W2117903449 @default.
• W961949223 cites W2121972108 @default.
• W961949223 cites W2124756133 @default.
• W961949223 cites W2128015661 @default.
• W961949223 cites W2128674168 @default.
• W961949223 cites W2129743050 @default.
• W961949223 cites W2129994868 @default.
• W961949223 cites W2132093971 @default.
• W961949223 cites W2137081126 @default.
• W961949223 cites W2137730290 @default.
• W961949223 cites W2139273728 @default.
• W961949223 cites W2139342290 @default.
• W961949223 cites W2139992910 @default.
• W961949223 cites W2141695132 @default.
• W961949223 cites W2142310248 @default.
• W961949223 cites W2143743183 @default.
• W961949223 cites W2145073911 @default.
• W961949223 cites W2145244611 @default.
• W961949223 cites W2146278947 @default.
• W961949223 cites W2148937727 @default.
• W961949223 cites W2150037286 @default.
• W961949223 cites W2155052345 @default.
• W961949223 cites W2155290141 @default.
• W961949223 cites W2155794059 @default.
• W961949223 cites W2156554003 @default.
• W961949223 cites W2156955518 @default.
• W961949223 cites W2157916750 @default.
• W961949223 cites W2160447597 @default.
• W961949223 cites W2161693225 @default.
• W961949223 cites W2162674813 @default.
• W961949223 cites W2162877470 @default.
• W961949223 cites W2166502047 @default.
• W961949223 cites W2167650832 @default.
• W961949223 cites W2171025829 @default.
• W961949223 cites W2172255406 @default.

• next